CA3165418A1

CA3165418A1 - Solid dosage forms containing bacteria and microbial extracellular vesicles

Info

Publication number: CA3165418A1
Application number: CA3165418A
Authority: CA
Inventors: Christopher J. H. Davitt; Brian Goodman; Syed Altaf
Original assignee: Evelo Biosciences Inc
Current assignee: Evelo Biosciences Inc
Priority date: 2019-12-27
Filing date: 2020-12-23
Publication date: 2021-07-01
Also published as: BR112022012514A2; KR20220128362A; WO2021133904A1; EP4081195A1; JP2023510158A; CN114945357A; TW202135783A; US20230355689A1; MX2022007943A; AR122353A1; CO2022010242A2; AU2020413225A1

Abstract

Enterically-coated solid dosage forms containing a pharmaceutical agent which includes bacteria and/or microbial extracellular vesicles (mEVs) are provided. Methods of treatment using such solid dosage forms are also provided.

Description

SOLID DOSAGE FORMS CONTAINING BACTERIA AND MICROBIAL
EXTRACELLULAR VESICLES
Cross-Reference to Related Applications [0001] This application claims the benefit of U.S. Provisional Application No.
62/954,153, filed on December 27, 2019; the entire contents of said application are incorporated herein in their entirety by this reference.
Summary

[0002] In certain aspects, provided herein are solid dosage forms of a pharmaceutical agent. In certain embodiments, such solid dose forms include capsules, tablets, and minitablets. In some embodiments, the capsules, tablets, or minitablets are coated with one layer of enteric coating or with two layers of enteric coatings (e.g., an inner enteric coating and an outer enteric coating). In some embodiments, the enterically-coated minitablets (with one layer of enteric coating or with two layers of enteric coatings) can be loaded into a capsule.

[0003] Aspects of the disclosure are based, in part, on the discovery that certain solid dosage forms of a pharmaceutical agent provide an increase in therapeutic efficacy and/or physiological effect as compared to other dosage forms of the pharmaceutical agent (e.g., as compared to the same dose of the pharmaceutical agent administered in a form that does not comprise the enteric coating, e.g., a non-enterically coated tablet or non-enterically coated minitablet or a suspension of biomass or powder). The solid dosage forms can be formulated to contain a lower dose (e.g., 1/10 or less of a dose) of the pharmaceutical agent than other dosage forms (e.g., as compared to the same dose of the pharmaceutical agent administered in a form that does not comprise the enteric coating, e.g., a non-enterically coated tablet or non-enterically coated minitablet or a suspension of biomass or powder), yet result in comparable therapeutic efficacy and/or physiological effect.
Such solid dosage forms can alternatively be formulated to contain the same dose of a pharmaceutical agent as other dosage forms (e.g., as compared to the same dose of the pharmaceutical agent administered in a form that does not comprise the enteric coating, e.g., a non-enterically coated tablet or non-enterically coated minitablet or a suspension of biomass or powder), yet result in greater therapeutic efficacy or physiological effect (e.g., 10-fold or more therapeutic efficacy or physiological effect). The solid dosage forms of a pharmaceutical

4 PCT/US2020/066828 agent as described herein can provide release in the small intestine of the pharmaceutical agent contained therein. The solid dosage forms can be prepared to allow release of the pharmaceutical agent at specific locations in the small intestine. Release of the pharmaceutical agent at particular locations in the small intestine allows the pharmaceutical agent to target and affect cells (e.g., epithelial cells and/or immune cells) located at these specific locations, e.g., which can cause a local effect in the gastrointestinal tract and/or cause a systemic effect (e.g., an effect outside of the gastrointestinal tract).
[0004] In certain embodiments, the solid dosage forms of a pharmaceutical agent as described herein can be used to deliver a variety of pharmaceutical agents that can act on immune cells and/or epithelial cells in the small intestine to cause a systemic effect (e.g., an effect outside of the gastrointestinal tract) and/or can cause a local effect in the gastrointestinal tract.

[0005] In some embodiments, the pharmaceutical agent can be of bacterial origin (e.g., mixture of selected strains or components thereof, such as microbial extracellular vesicles (mEVs) of the mixture of selected strains). The pharmaceutical agent can be of bacterial origin (e.g., a single selected strain and/or components thereof, such as microbial extracellular vesicles (mEVs) of that single selected strain).

[0006] As described herein, improved therapeutic effects were seen with certain solid dosage forms of a pharmaceutical agent that contained one layer of enteric coating, as compared to the same dose of the pharmaceutical agent administered in a form that does not comprise the enteric coating, e.g., a non-enterically coated tablet or non-enterically coated minitablet or a suspension of biomass or powder.

[0007] In some embodiments, a solid dosage form described herein can provide, inter alia, a pharmaceutical agent (e.g., a formulation of a pharmaceutical agent) which enhances the pharmacological potency of the pharmaceutical agent by 10-fold or more in preclinical in vivo models, as compared to the same dose of the pharmaceutical agent administered in a form that does not comprise the enteric coating, e.g., a non-enterically coated tablet or non-enterically coated minitablet or a suspension of biomass or powder).
For example, for a given level of therapeutic efficacy and/or physiological effect obtained with a comparator formulation of the pharmaceutical agent, the dose can be reduced (e.g., to 1/10 or less) when prepared in a solid dosage form described herein.

[0008] In some embodiments, or a given dose of a pharmaceutical agent, target engagement (e.g., in the small intestine) can be increased such that for a given dose of a pharmaceutical agent, target engagement (e.g., in the small intestine) can be increased for better efficacy when the pharmaceutical agent is prepared in a solid dosage form described herein.

[0009] In some aspects, the disclosure provides a solid dosage form (e.g., for oral administration) (e.g., for therapeutic use) comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated (e.g., comprises an enteric coating; e.g., is coated with an enteric coating).

[0010] In certain embodiments, the solid dosage form comprises a capsule.
In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
In some embodiments, the capsule is a size 0 capsule.

[0011] In some embodiments, the solid dosage form comprises a tablet. In some embodiments, the tablet (e.g., enterically coated tablet) is a 5mm, 6mm, 7mm, 8mm, 9mm, lOmm, llmm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, or 18mm tablet.

[0012] In some embodiments, the solid dosage form comprises a minitablet.
In some embodiments, the minitablet (e.g., enterically coated minitablet) is a lmm minitablet, 1.5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet. In some embodiments, a plurality of enterically coated minitablets are contained in a capsule (e.g., a size 0 capsule can contain about 31 to about 35 (e.g., 33) minitablets, wherein the minitablets are 3mm in size). In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. In some embodiments, the capsule comprises HPMC
(hydroxyl propyl methyl cellulose) or gelatin.

[0013] In some embodiments, the enteric coating comprises one enteric coating.

[0014] In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not identical (e.g., the inner and outer enteric coatings do not contain identical components in identical amounts).

[0015] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a polymethacrylate-based copolymer.

[0016] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

[0017] In some embodiments, the one enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[0018] In some embodiments, the one enteric coating comprises a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS
30 D).

[0019] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

[0020] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises an anionic polymeric material.

[0021] In some embodiments, the solid dosage form comprises a sub-coat, e.g., under the enteric coating (e.g., one enteric coating). The sub-coat can be used, e.g., to visually mask the appearance of the pharmaceutical agent.

[0022] In some embodiments, the pharmaceutical agent comprises bacteria.

[0023] In some embodiments, the pharmaceutical agent comprises microbial extracellular vesicles (mEV).

[0024] In some embodiments, the pharmaceutical agent comprises bacteria and microbial extracellular vesicles (mEV).

[0025] In some embodiments, the pharmaceutical agent has one or more beneficial immune effects outside the gastrointestinal tract, e.g., when the solid dosage form is orally administered.

[0026] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract (e.g., outside of the small intestine) in the subject, e.g., when the solid dosage form is orally administered.

[0027] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[0028] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[0029] In some embodiments, the pharmaceutical agent comprises isolated bacteria (e.g., from one or more strains of bacteria (e.g., bacteria of interest) (e.g., a therapeutically effective amount thereof)). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is the isolated bacteria (e.g., bacteria of interest).

[0030] In some embodiments, the pharmaceutical agent comprises bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

[0031] In some embodiments, the pharmaceutical agent comprises live bacteria.

[0032] In some embodiments, the pharmaceutical agent comprises dead bacteria.

[0033] In some embodiments, the pharmaceutical agent comprises non-replicating bacteria.

[0034] In some embodiments, the pharmaceutical agent comprises bacteria from one strain of bacteria.

[0035] In some embodiments, the bacteria are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient) (e.g., a powder form).

[0036] In some embodiments, the bacteria are gamma irradiated.

[0037] In some embodiments, the bacteria are UV irradiated.

[0038] In some embodiments, the bacteria are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).

[0039] In some embodiments, the bacteria are acid treated.

[0040] In some embodiments, the bacteria are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0041] In some embodiments, the bacteria are Gram positive bacteria.

[0042] In some embodiments, the bacteria are Gram negative bacteria.

[0043] In some embodiments, the bacteria are aerobic bacteria.

[0044] In some embodiments, the bacteria are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0045] In some embodiments, the bacteria are acidophile bacteria.

[0046] In some embodiments, the bacteria are alkaliphile bacteria.

[0047] In some embodiments, the bacteria are neutralophile bacteria.

[0048] In some embodiments, the bacteria are fastidious bacteria.

[0049] In some embodiments, the bacteria are nonfastidious bacteria.

[0050] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0051] In some embodiments, the bacteria are a bacterial strain listed in Table 1, Table 2, or Table 3.

[0052] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0053] In some embodiments, the bacteria are a bacterial strain listed in Table J.

[0054] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0055] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae .

[0056] In some embodiments, the bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0057] In some embodiments, the bacteria are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0058] In some embodiments, the bacteria are of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one/la.

[0059] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.

[0060] In some embodiments, the bacteria are Prevotella histicola bacteria.

[0061] In some embodiments, the bacteria are Bifidobacterium animalis bacteria.

[0062] In some embodiments, the bacteria are Veil/one/la parvula bacteria.

[0063] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.
In some embodiments, the Lactococcus lactis cremoris bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0064] In some embodiments, the bacteria are Prevotella bacteria. In some embodiments, the Prevotella bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are Prevotella Strain B 50329 (NRRL accession number B 50329).

[0065] In some embodiments, the bacteria are Bifidobacterium bacteria. In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are Bifidobacterium bacteria deposited as ATCC
designation number PTA-125097.

[0066] In some embodiments, the bacteria are Veillonella bacteria. In some embodiments, the Veillonella bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veillonella bacteria are a strain comprising at least 99%
genomic, 16S
and/or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veillonella bacteria are Veillonella bacteria deposited as ATCC designation number PTA-125691.

[0067] In some embodiments, the bacteria are from Ruminococcus gnavus bacteria.
In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0068] In some embodiments, the bacteria are Megasphaera sp. bacteria. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are Megasphaera sp. bacteria deposited as ATCC
designation number PTA-126770.

[0069] In some embodiments, the bacteria are Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696.

[0070] In some embodiments, the bacteria are Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[0071] In some embodiments, the bacteria are of the family Acidaminococcaceae, Alcaligenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae .

[0072] In some embodiments, the bacteria are of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0073] In some embodiments, the bacteria are Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium an/malls, or Bifidobacterium breve bacteria.

[0074] In some embodiments, the bacteria are BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[0075] In some embodiments, the bacteria are Blautia hydrogenotrophica bacteria.

[0076] In some embodiments, the bacteria are Blautia stercoris bacteria.

[0077] In some embodiments, the bacteria are Blautia w exlerae bacteria.

[0078] In some embodiments, the bacteria are Enterococcus gallinarum bacteria.

[0079] In some embodiments, the bacteria are Enterococcus faecium bacteria.

[0080] In some embodiments, the bacteria are Bifidobacterium bifidium bacteria.

[0081] In some embodiments, the bacteria are Bifidobacterium breve bacteria.

[0082] In some embodiments, the bacteria are Bifidobacterium longum bacteria.

[0083] In some embodiments, the bacteria are Roseburia hominis bacteria.

[0084] In some embodiments, the bacteria are Bacteroides thetaiotaomicron bacteria.

[0085] In some embodiments, the bacteria are Bacteroides coprocola bacteria.

[0086] In some embodiments, the bacteria are Erysipelatoclostridium ramosum bacteria.

[0087] In some embodiments, the bacteria are Megasphera massiliensis bacteria.

[0088] In some embodiments, the bacteria are Eubacterium bacteria.

[0089] In some embodiments, the bacteria are Parabacteroides distasonis bacteria.

[0090] In some embodiments, the bacteria are Lactobacillus plantarum bacteria.

[0091] In some embodiments, the bacteria are bacteria of the Negativicutes class.

[0092] In some embodiments, the bacteria are of the Veillonellaceae family.

[0093] In some embodiments, the bacteria are of the Selenomonadaceae family.

[0094] In some embodiments, the bacteria are of the Acidaminococcaceae family.

[0095] In some embodiments, the bacteria are of the Sporomusaceae family.

[0096] In some embodiments, the bacteria are of the Megasphaera genus.

[0097] In some embodiments, the bacteria are of the Selenomonas genus.

[0098] In some embodiments, the bacteria are of the Propionospora genus.

[0099] In some embodiments, the bacteria are of the Acidaminococcus genus.

[0100] In some embodiments, the bacteria are Megasphaera sp. bacteria.

[0101] In some embodiments, the bacteria are Selenomonas felix bacteria.

[0102] In some embodiments, the bacteria are Acidaminococcus intestini bacteria.

[0103] In some embodiments, the bacteria are Propionospora sp. bacteria.

[0104] In some embodiments, the bacteria are bacteria of the Clostridia class.

[0105] In some embodiments, the bacteria are of the Oscillospriraceae family.

[0106] In some embodiments, the bacteria are of the Faecalibacterium genus.

[0107] In some embodiments, the bacteria are of the Fournierella genus.

[0108] In some embodiments, the bacteria are of the Harryflintia genus.

[0109] In some embodiments, the bacteria are of the Agathobaculum genus.

[0110] In some embodiments, the bacteria are Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[0111] In some embodiments, the bacteria are Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[0112] In some embodiments, the bacteria are Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[0113] In some embodiments, the bacteria are Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[0114] In some embodiments, the bacteria are a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[0115] In some embodiments, the bacteria are of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the bacteria are of order Bacteroidales.
In some embodiments, the bacteria are of the family Porphyromonoadaceae. In some embodiments, the bacteria are of the family Prevotellaceae. In some embodiments, the bacteria are of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Bacteroidia that stain Gram negative. In some embodiments, the bacteria are of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[0116] In some embodiments, the bacteria are of the class Clostridia [phylum Firmicutes]. In some embodiments, the bacteria are of the order Eubacteriales.
In some embodiments, the bacteria are of the family Oscillispiraceae. In some embodiments, the bacteria are of the family Lachnospiraceae. In some embodiments, the bacteria are of the family Peptostreptococcaceae. In some embodiments, the bacteria are of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the bacteria are of the class Clostridia that stain Gram negative. In some embodiments, the bacteria are of the class Clostridia that stain Gram positive. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[0117] In some embodiments, the bacteria are of the class Negativicutes [phylum Firmicutes]. In some embodiments, the bacteria are of the order Veil/one/la/es. In some embodiments, the bacteria are of the family Veillonelloceae. In some embodiments, the bacteria are of the order Selenomonadales. In some embodiments, the bacteria are of the family Selenomonadaceae. In some embodiments, the bacteria are of the family Sporomusaceae. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Negativicutes that stain Gram negative. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0118] In some embodiments, the bacteria are of the class Synergistia [phylum Synergistota]. In some embodiments, the bacteria are of the order Synergi stales. In some embodiments, the bacteria are of the family Synergistaceae. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Synergistia that stain Gram negative. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0119] In some embodiments, the bacteria are bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[0120] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[0121] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or 0/send/a.

[0122] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veil/one/la.

[0123] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[0124] In some embodiments, the bacteria are bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[0125] In some embodiments, the pharmaceutical agent comprises isolated mEVs (e.g., from one or more strains of bacteria (e.g., bacteria of interest)) (e.g., a therapeutically effective amount thereof). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is isolated mEV of bacteria (e.g., bacteria of interest).

[0126] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise secreted mEVs (smEVs).

[0127] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise processed mEVs (pmEVs).

[0128] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from bacteria that have been gamma irradiated, UV
irradiated, heat inactivated, acid treated, or oxygen sparged.

[0129] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from live bacteria.

[0130] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from dead bacteria.

[0131] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from non-replicating bacteria.

[0132] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs are from one strain of bacteria.

[0133] In some embodiments, the mEVs are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient).

[0134] In some embodiments, the mEVs are gamma irradiated.

[0135] In some embodiments, the mEVs are UV irradiated.

[0136] In some embodiments, the mEVs are heat inactivated (e.g., at 50 C
for two hours or at 90 C for two hours).

[0137] In some embodiments, the mEVs are acid treated.

[0138] In some embodiments, the mEVs are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0139] In some embodiments, the mEVs are from Gram positive bacteria.

[0140] In some embodiments, the mEVs are from Gram negative bacteria.

[0141] In some embodiments, the mEVs are from aerobic bacteria.

[0142] In some embodiments, the mEVs are from anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0143] In some embodiments, the mEVs are from acidophile bacteria.

[0144] In some embodiments, the mEVs are from alkaliphile bacteria.

[0145] In some embodiments, the mEVs are from neutralophile bacteria.

[0146] In some embodiments, the mEVs are from fastidious bacteria.

[0147] In some embodiments, the mEVs are from nonfastidious bacteria.

[0148] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0149] In some embodiments, the mEVs are from a bacterial strain listed in Table 1, Table 2, or Table 3.

[0150] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0151] In some embodiments, the mEVs are from a bacterial strain listed in Table J.

[0152] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0153] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae .

[0154] In some embodiments, the mEVs are from bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0155] In some embodiments, the mEVs are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0156] In some embodiments, the mEVs are from bacteria of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one/la.

[0157] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria.

[0158] In some embodiments, the mEVs are from Prevotella histicola bacteria.

[0159] In some embodiments, the mEVs are from Bifidobacterium animalis bacteria.

[0160] In some embodiments, the mEVs are from Veil/one/la parvula bacteria.

[0161] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria. In some embodiments, the Lactococcus lactis cremoris bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0162] In some embodiments, the mEVs are from Prevotella bacteria. In some embodiments, the Prevotella bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are from a strain comprising at least 99% genomic, 16S
and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are from Prevotella Strain B 50329 (NRRL accession number B 50329).

[0163] In some embodiments, the mEVs are from Bifidobacterium bacteria.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are from Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.

[0164] In some embodiments, the mEVs are from Veillonella bacteria. In some embodiments, the Veillonella bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veillonella bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from Veil/one/la bacteria deposited as ATCC
designation number PTA-125691.

[0165] In some embodiments, the mEVs are from Ruminococcus gnavus bacteria. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0166] In some embodiments, the mEVs are from Megasphaera sp. bacteria.
In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770.
In some embodiments, the Megasphaera sp. bacteria are from Megasphaera sp.
bacteria deposited as ATCC designation number PTA-126770.

[0167] In some embodiments, the mEVs are from Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696.

[0168] In some embodiments, the mEVs are from Harryflintia acetispora bacteria.
In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[0169] In some embodiments, the mEVs are from bacteria of the family Acidaminococcaceae, Alcaligenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae.

[0170] In some embodiments, the mEVs are from bacteria of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0171] In some embodiments, the mEVs are from Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium an/malls, or Bifidobacterium breve bacteria.

[0172] In some embodiments, the mEVs are from BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[0173] In some embodiments, the mEVs are from Blautia hydrogenotrophica bacteria.

[0174] In some embodiments, the mEVs are from Blautia stercoris bacteria.

[0175] In some embodiments, the mEVs are from Blautia wexlerae bacteria.

[0176] In some embodiments, the mEVs are from Enterococcus galhnarum bacteria.

[0177] In some embodiments, the mEVs are from Enterococcus faecium bacteria.

[0178] In some embodiments, the mEVs are from Bifidobacterium bifidium bacteria.

[0179] In some embodiments, the mEVs are from Bifidobacterium breve bacteria.

[0180] In some embodiments, the mEVs are from Bifidobacterium longum bacteria.

[0181] In some embodiments, the mEVs are from Roseburia hominis bacteria.

[0182] In some embodiments, the mEVs are from Bacteroides thetaiotaomicron bacteria.

[0183] In some embodiments, the mEVs are from Bacteroides coprocola bacteria.

[0184] In some embodiments, the mEVs are from Erysipelatoclostridium ramosum bacteria.

[0185] In some embodiments, the mEVs are from Megasphera massiliensis bacteria.

[0186] In some embodiments, the mEVs are from Eubacterium bacteria.

[0187] In some embodiments, the mEVs are from Parabacteroides distasonis bacteria.

[0188] In some embodiments, the mEVs are from Lactobacillus plantarum bacteria.

[0189] In some embodiments, the mEVs are from bacteria of the Negativicutes class.

[0190] In some embodiments, the mEVs are from bacteria of the Veillonellaceae family.

[0191] In some embodiments, the mEVs are from bacteria of the Selenomonadaceae family.

[0192] In some embodiments, the mEVs are from bacteria of the Acidaminococcaceae family.

[0193] In some embodiments, the mEVs are from bacteria of the Sporomusaceae family.

[0194] In some embodiments, the mEVs are from bacteria of the Megasphaera genus.

[0195] In some embodiments, the mEVs are from bacteria of the Selenomonas genus.

[0196] In some embodiments, the mEVs are from bacteria of the Propionospora genus.

[0197] In some embodiments, the mEVs are from bacteria of the Acidaminococcus genus.

[0198] In some embodiments, the mEVs are from Megasphaera sp. bacteria.

[0199] In some embodiments, the mEVs are from Selenomonas felix bacteria.

[0200] In some embodiments, the mEVs are from Acidaminococcus intestini bacteria.

[0201] In some embodiments, the mEVs are from Propionospora sp. bacteria.

[0202] In some embodiments, the mEVs are from bacteria of the Clostridia class.

[0203] In some embodiments, the mEVs are from bacteria of the Oscillospriraceae family.

[0204] In some embodiments, the mEVs are from bacteria of the Faecalibacterium genus.

[0205] In some embodiments, the mEVs are from bacteria of the Fournierella genus.

[0206] In some embodiments, the mEVs are from bacteria of the Harryflintia genus.

[0207] In some embodiments, the mEVs are from bacteria of the Agathobaculum genus.

[0208] In some embodiments, the mEVs are from Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[0209] In some embodiments, the mEVs are from Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[0210] In some embodiments, the mEVs are from Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[0211] In some embodiments, the mEVs are from Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[0212] In some embodiments, the mEVs are from a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.

Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[0213] In some embodiments, the mEVs are from bacteria of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the mEVs are from bacteria of order Bacteroidales. In some embodiments, the mEVs are from bacteria of the family Porphyromonoadaceae. In some embodiments, the mEVs are from bacteria of the family Prevotellaceae. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Bacteroidia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[0214] In some embodiments, the mEVs are from bacteria of the class Clostridia [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Eubacteriales. In some embodiments, the mEVs are from bacteria of the family Oscillispiraceae. In some embodiments, the mEVs are from bacteria of the family Lachnospiraceae. In some embodiments, the mEVs are from bacteria of the family Peptostreptococcaceae. In some embodiments, the mEVs are from bacteria of the family Clostridiales family XIII/ Incertae sec/is 41. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram positive. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[0215] In some embodiments, the mEVs are from bacteria of the class Negativicutes [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Veil/one/la/es. In some embodiments, the mEVs are from bacteria of the family Veillonelloceae. In some embodiments, the mEVs are from bacteria of the order Selenomonadales. In some embodiments, the mEVs are from bacteria of the family Selenomonadaceae. In some embodiments, the mEVs are from bacteria of the family Sporomusaceae. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm.
In some embodiments, the mEVs are from bacteria of the class Negativicutes that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0216] In some embodiments, the mEVs are from bacteria of the class Synergistia [phylum Synergistota]. In some embodiments, the mEVs are from bacteria of the order Synergistales. In some embodiments, the mEVs are from bacteria of the family Synergistaceae. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Synergistia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0217] In some embodiments, the mEVs are from bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[0218] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[0219] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[0220] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[0221] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[0222] In some embodiments, the mEVs are from bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus mass/liens/s, Faecal/bacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[0223] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 107 to about 2 x 1012 (e.g., about 3 x 1010 or about 1.5 x 1011 or about 1.5 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 1010 to about 2 x 1012 (e.g., about 1.6 x 1011 or about 8 x 1011 or about 9.6 x 1011 about 12.8 x 1011 or about 1.6 x 1012) cells (e.g., wherein cell number is determined by total cell count, e.g., as determined by Coulter counter), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0224] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 109, about 3 x 109, about 5 x 109, about 1.5 x 1010, about 3 x 1010, about 5 x 1010, about 1.5 x 1011, about 1.5 x 1012, or about 2 x 1012 cells, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0225] In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 105 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 1010 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0226] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 10 mg to about 3500 mg, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0227] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 30 mg to about 1300 mg (by weight of bacteria and/or mEVs) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0228] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 2x106 to about 2x1016 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0229] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 5 mg to about 900 mg total protein (e.g., wherein total protein is determined by Bradford assay or BCA), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0230] In some embodiments, the solid dosage form further comprises one or more additional pharmaceutical agents.

[0231] In some embodiments, the solid dosage form further comprises an excipient (e.g., an excipient described herein, e.g., a diluent, a binder and/or an adhesive, a disintegrant, a lubricant and/or a glidant, a coloring agent, a flavoring agent, and/or a sweetening agent).

[0232] In some aspects, the disclosure provides a method of treating a subject (e.g., human) (e.g., a subject in need of treatment), the method comprising:

[0233] administering to the subject a solid dosage form, wherein the solid dosage form comprises a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated (e.g., comprises an enteric coating; e.g., is coated with an enteric coating).

[0234] In some aspects, the disclosure provides a solid dosage form for use in treating a subject (e.g., human) (e.g., a subject in need of treatment), wherein the solid dosage form comprises a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated (e.g., comprises an enteric coating; e.g., is coated with an enteric coating).

[0235] In some aspects, the disclosure provides use of a solid dosage form for the preparation of a medicament for treating a subject (e.g., human) (e.g., a subject in need of treatment), wherein the solid dosage form comprises a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated (e.g., comprises an enteric coating; e.g., is coated with an enteric coating).

[0236] In some embodiments, the solid dosage form is orally administered (e.g., is for oral administration).

[0237] In some embodiments, the solid dosage form (e.g., a capsule, a tablet, or a plurality of minitablets (e.g., contained in a capsule)) is administered (e.g., is for administration) 1, 2, 3, or 4 times a day.

[0238] In some embodiments, the solid dosage form comprises a capsule, a tablet, or a plurality of minitablets (e.g., contained in a capsule) and 1, 2, 3, or 4 solid dosage forms (e.g., a capsule, a tablet, or a plurality of minitablets (e.g., contained in a capsule)) are administered (e.g., are for administration) 1, 2, 3, or 4 times a day.

[0239] In some embodiments, the solid dosage form provides an increase in efficacy or in physiological effect of the pharmaceutical agent (e.g., 10-fold or more) as compared to other dosage forms (e.g., as compared to the same dose of the pharmaceutical agent administered in a form that does not comprise the enteric coating, e.g., a non-enterically coated tablet or non-enterically coated minitablet or a suspension of biomass or powder).

[0240] In some embodiments, the solid dosage form provides release in the small intestine of the pharmaceutical agent contained in the solid dosage form.

[0241] In some embodiments, the solid dosage form delivers the pharmaceutical agent to the small intestine, wherein the pharmaceutical agent can act on immune cells and/or epithelial cells in the small intestine, e.g., to cause a systemic effect (e.g., an effect outside of the gastrointestinal tract).

[0242] In some embodiments, the solid dosage form provides increased efficacy or increased physiological effect (10-fold or more increased efficacy) (e.g., as measured by a systemic effect (e.g., outside of the gastrointestinal tract) of the pharmaceutical agent, e.g., in ear thickness in DTH model for inflammation; tumor size in cancer model), e.g., as compared to the same dose of the pharmaceutical agent administered in a form that does not comprise the enteric coating, e.g., a suspension or non-enterically coated tablet or non-enterically coated minitablet).

[0243] In some embodiments, the pharmaceutical agent provides one or more beneficial immune effects outside the gastrointestinal tract (e.g., outside of the small intestine), e.g., when orally administered.

[0244] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract (e.g., outside of the small intestine) in the subject, e.g., when orally administered.

[0245] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when orally administered.

[0246] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine (e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinal tract)), e.g., when orally administered.

[0247] In some embodiments, the solid dosage form is administered orally and has one or more beneficial immune effects outside the gastrointestinal tract (e.g., interaction between the pharmaceutical agent and cells in the small intestine modulates a systemic immune response).

[0248] In some embodiments, the solid dosage form is administered orally and modulates immune effects outside the gastrointestinal tract (e.g., interaction between agent and cells in the small intestine modulates a systemic immune response).

[0249] In some embodiments, the solid dosage form is administered orally and activates innate antigen presenting cells (e.g., in the small intestine).

[0250] In some embodiments, the subject is in need of treatment (and/or prevention) of a cancer.

[0251] In some embodiments, the subject is in need of treatment (and/or prevention) of an autoimmune disease.

[0252] In some embodiments, the subject is in need of treatment (and/or prevention) of an inflammatory disease.

[0253] In some embodiments, the subject is in need of treatment (and/or prevention) of a metabolic disease.

[0254] In some embodiments, the subject is in need of treatment (and/or prevention) of dysbiosis.

[0255] In some embodiments, the solid dosage form is administered in combination with an additional pharmaceutical agent.

[0256] In certain embodiments, the solid dosage form comprises a capsule.
In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
In some embodiments, the capsule is a size 0 capsule.

[0257] In some embodiments, the solid dosage form comprises a tablet. In some embodiments, the tablet (e.g., enterically coated tablet) is a 5mm, 6mm, 7mm, 8mm, 9mm, lOmm, llmm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, or 18mm tablet.

[0258] In some embodiments, the solid dosage form comprises a minitablet.
In some embodiments, the minitablet (e.g., enterically coated minitablet) is a lmm minitablet, 1.5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet. In some embodiments, a plurality of enterically coated minitablets are contained in a capsule (e.g., a size 0 capsule can contain about 31 to about 35 (e.g., 33) minitablets, wherein the minitablets are 3mm in size). In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. In some embodiments, the capsule comprises HPMC
(hydroxyl propyl methyl cellulose) or gelatin.

[0259] In some embodiments, the enteric coating comprises one enteric coating.

[0260] In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not identical (e.g., the inner and outer enteric coatings do not contain identical components in identical amounts).

[0261] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a polymethacrylate-based copolymer.

[0262] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

[0263] In some embodiments, the one enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[0264] In some embodiments, the one enteric coating comprises a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS
30 D).

[0265] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

[0266] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises an anionic polymeric material.

[0267] In some embodiments, the pharmaceutical agent agent comprises bacteria.

[0268] In some embodiments, the pharmaceutical agent comprises microbial extracellular vesicles (mEV).

[0269] In some embodiments, the pharmaceutical agent comprises bacteria and microbial extracellular vesicles (mEV).

[0270] In some embodiments, the pharmaceutical agent has one or more beneficial immune effects outside the gastrointestinal tract, e.g., when the solid dosage form is orally administered.

[0271] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract (e.g., outside of the small intestine) in the subject, e.g., when the solid dosage form is orally administered.

[0272] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[0273] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine (e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinal tract)), e.g., when the solid dosage form is orally administered.

[0274] In some embodiments, the pharmaceutical agent comprises isolated bacteria (e.g., from one or more strains of bacteria (e.g., bacteria of interest) (e.g., a therapeutically effective amount thereof)). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is the isolated bacteria (e.g., bacteria of interest).

[0275] In some embodiments, the pharmaceutical agent comprises bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

[0276] In some embodiments, the pharmaceutical agent comprises live bacteria.

[0277] In some embodiments, the pharmaceutical agent comprises dead bacteria.

[0278] In some embodiments, the pharmaceutical agent comprises non-replicating bacteria.

[0279] In some embodiments, the pharmaceutical agent comprises bacteria from one strain of microbe (e.g., bacteria).

[0280] In some embodiments, the bacteria are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient) (e.g., a powder form).

[0281] In some embodiments, the bacteria are gamma irradiated.

[0282] In some embodiments, the bacteria are UV irradiated.

[0283] In some embodiments, the bacteria are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).

[0284] In some embodiments, the bacteria are acid treated.

[0285] In some embodiments, the bacteria are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0286] In some embodiments, the bacteria are Gram positive bacteria.

[0287] In some embodiments, the bacteria are Gram negative bacteria.

[0288] In some embodiments, the bacteria are aerobic bacteria.

[0289] In some embodiments, the bacteria are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0290] In some embodiments, the bacteria are acidophile bacteria.

[0291] In some embodiments, the bacteria are alkaliphile bacteria.

[0292] In some embodiments, the bacteria are neutralophile bacteria.

[0293] In some embodiments, the bacteria are fastidious bacteria.

[0294] In some embodiments, the bacteria are nonfastidious bacteria.

[0295] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0296] In some embodiments, the bacteria are a bacterial strain listed in Table 1, Table 2, or Table 3.

[0297] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0298] In some embodiments, the bacteria are a bacterial strain listed in Table J.

[0299] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0300] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae.

[0301] In some embodiments, the bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0302] In some embodiments, the bacteria are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0303] In some embodiments, the bacteria are of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one/la.

[0304] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.

[0305] In some embodiments, the bacteria are Prevotella histicola bacteria.

[0306] In some embodiments, the bacteria are Bifidobacterium animalis bacteria.

[0307] In some embodiments, the bacteria are Veil/one/la parvula bacteria.

[0308] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.
In some embodiments, the Lactococcus lactis cremoris bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0309] In some embodiments, the bacteria are Prevotella bacteria. In some embodiments, the Prevotella bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are Prevotella Strain B 50329 (NRRL accession number B 50329).

[0310] In some embodiments, the bacteria are Bifidobacterium bacteria. In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are Bifidobacterium bacteria deposited as ATCC
designation number PTA-125097.

[0311] In some embodiments, the bacteria are Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 99%
genomic, 16S
and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are Veil/one/la bacteria deposited as ATCC designation number PTA-125691.

[0312] In some embodiments, the bacteria are from Ruminococcus gnavus bacteria.
In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0313] In some embodiments, the bacteria are Megasphaera sp. bacteria. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are Megasphaera sp. bacteria deposited as ATCC
designation number PTA-126770.

[0314] In some embodiments, the bacteria are Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696.

[0315] In some embodiments, the bacteria are Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[0316] In some embodiments, the bacteria are of the family Acidaminococcaceae, Alcaligenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae .

[0317] In some embodiments, the bacteria are of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0318] In some embodiments, the bacteria are Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium animalis, or Bifidobacterium breve bacteria.

[0319] In some embodiments, the bacteria are BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[0320] In some embodiments, the bacteria are Blautia hydrogenotrophica bacteria.

[0321] In some embodiments, the bacteria are Blautia stercoris bacteria.

[0322] In some embodiments, the bacteria are Blautia w exlerae bacteria.

[0323] In some embodiments, the bacteria are Enterococcus galhnarum bacteria.

[0324] In some embodiments, the bacteria are Enterococcus faecium bacteria.

[0325] In some embodiments, the bacteria are Bifidobacterium bifidium bacteria.

[0326] In some embodiments, the bacteria are Bifidobacterium breve bacteria.

[0327] In some embodiments, the bacteria are Bifidobacterium longum bacteria.

[0328] In some embodiments, the bacteria are Roseburia hominis bacteria.

[0329] In some embodiments, the bacteria are Bacteroides thetaiotaomicron bacteria.

[0330] In some embodiments, the bacteria are Bacteroides coprocola bacteria.

[0331] In some embodiments, the bacteria are Erysipelatoclostridium ramosum bacteria.

[0332] In some embodiments, the bacteria are Megasphera massiliensis bacteria.

[0333] In some embodiments, the bacteria are Eubacterium bacteria.

[0334] In some embodiments, the bacteria are Parabacteroides distasonis bacteria.

[0335] In some embodiments, the bacteria are Lactobacillus plantarum bacteria.

[0336] In some embodiments, the bacteria are bacteria of the Negativicutes class.

[0337] In some embodiments, the bacteria are of the Veillonellaceae family.

[0338] In some embodiments, the bacteria are of the Selenomonadaceae family.

[0339] In some embodiments, the bacteria are of the Acidaminococcaceae family.

[0340] In some embodiments, the bacteria are of the Sporomusaceae family.

[0341] In some embodiments, the bacteria are of the Megasphaera genus.

[0342] In some embodiments, the bacteria are of the Selenomonas genus.

[0343] In some embodiments, the bacteria are of the Propionospora genus.

[0344] In some embodiments, the bacteria are of the Acidaminococcus genus.

[0345] In some embodiments, the bacteria are Megasphaera sp. bacteria.

[0346] In some embodiments, the bacteria are Selenomonas felix bacteria.

[0347] In some embodiments, the bacteria are Acidaminococcus intestini bacteria.

[0348] In some embodiments, the bacteria are Propionospora sp. bacteria.

[0349] In some embodiments, the bacteria are bacteria of the Clostridia class.

[0350] In some embodiments, the bacteria are of the Oscillospriraceae family.

[0351] In some embodiments, the bacteria are of the Faecalibacterium genus.

[0352] In some embodiments, the bacteria are of the Fournierella genus.

[0353] In some embodiments, the bacteria are of the Harryflintia genus.

[0354] In some embodiments, the bacteria are of the Agathobaculum genus.

[0355] In some embodiments, the bacteria are Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[0356] In some embodiments, the bacteria are Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[0357] In some embodiments, the bacteria are Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[0358] In some embodiments, the bacteria are Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[0359] In some embodiments, the bacteria are a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[0360] In some embodiments, the bacteria are of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the bacteria are of order Bacteroidales.
In some embodiments, the bacteria are of the family Porphyromonoadaceae . In some embodiments, the bacteria are of the family Prevotellaceae . In some embodiments, the bacteria are of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Bacteroidia that stain Gram negative. In some embodiments, the bacteria are of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[0361] In some embodiments, the bacteria are of the class Clostridia [phylum Firmicutes]. In some embodiments, the bacteria are of the order Eubacteriales.
In some embodiments, the bacteria are of the family Oscillispiraceae. In some embodiments, the bacteria are of the family Lachnospiraceae. In some embodiments, the bacteria are of the family Peptostreptococcaceae. In some embodiments, the bacteria are of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the bacteria are of the class Clostridia that stain Gram negative. In some embodiments, the bacteria are of the class Clostridia that stain Gram positive. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[0362] In some embodiments, the bacteria are of the class Negativicutes [phylum Firmicutes]. In some embodiments, the bacteria are of the order Veillonellales. In some embodiments, the bacteria are of the family Veillonelloceae. In some embodiments, the bacteria are of the order Selenomonadales. In some embodiments, the bacteria are of the family Selenomonadaceae. In some embodiments, the bacteria are of the family Sporomusaceae. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Negativicutes that stain Gram negative. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0363] In some embodiments, the bacteria are of the class Synergistia [phylum Synergistota]. In some embodiments, the bacteria are of the order Synergi stales. In some embodiments, the bacteria are of the family Synergistaceae. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Synergistia that stain Gram negative. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0364] In some embodiments, the bacteria are bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[0365] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[0366] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[0367] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[0368] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[0369] In some embodiments, the bacteria are bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[0370] In some embodiments, the pharmaceutical agent comprises isolated mEVs (e.g., from one or more strains of bacteria (e.g., bacteria of interest)) (e.g., a therapeutically effective amount thereof). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is isolated mEV of bacteria (e.g., bacteria of interest).

[0371] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise secreted mEVs (smEVs).

[0372] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise processed mEVs (pmEVs).

[0373] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from bacteria that have been gamma irradiated, UV
irradiated, heat inactivated, acid treated, or oxygen sparged.

[0374] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from live bacteria.

[0375] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from dead bacteria.

[0376] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from non-replicating bacteria.

[0377] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs are from one strain of bacteria.

[0378] In some embodiments, the mEVs are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient).

[0379] In some embodiments, the mEVs are gamma irradiated.

[0380] In some embodiments, the mEVs are UV irradiated.

[0381] In some embodiments, the mEVs are heat inactivated (e.g., at 50 C
for two hours or at 90 C for two hours).

[0382] In some embodiments, the mEVs are acid treated.

[0383] In some embodiments, the mEVs are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0384] In some embodiments, the mEVs are from Gram positive bacteria.

[0385] In some embodiments, the mEVs are from Gram negative bacteria.

[0386] In some embodiments, the mEVs are from aerobic bacteria.

[0387] In some embodiments, the mEVs are from anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0388] In some embodiments, the mEVs are from acidophile bacteria.

[0389] In some embodiments, the mEVs are from alkaliphile bacteria.

[0390] In some embodiments, the mEVs are from neutralophile bacteria.

[0391] In some embodiments, the mEVs are from fastidious bacteria.

[0392] In some embodiments, the mEVs are from nonfastidious bacteria.

[0393] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0394] In some embodiments, the mEVs are from a bacterial strain listed in Table 1, Table 2, or Table 3.

[0395] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0396] In some embodiments, the mEVs are from a bacterial strain listed in Table J.

[0397] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0398] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae.

[0399] In some embodiments, the mEVs are from bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0400] In some embodiments, the mEVs are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0401] In some embodiments, the mEVs are from bacteria of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one//a.

[0402] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria.

[0403] In some embodiments, the mEVs are from Prevotella histicola bacteria.

[0404] In some embodiments, the mEVs are from Bifidobacterium animalis bacteria.

[0405] In some embodiments, the mEVs are from Veil/one/la parvula bacteria.

[0406] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria. In some embodiments, the Lactococcus lactis cremoris bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0407] In some embodiments, the mEVs are from Prevotella bacteria. In some embodiments, the Prevotella bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are from a strain comprising at least 99% genomic, 16S
and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are from Prevotella Strain B 50329 (NRRL accession number B 50329).

[0408] In some embodiments, the mEVs are from Bifidobacterium bacteria.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are from Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.

[0409] In some embodiments, the mEVs are from Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from Veil/one/la bacteria deposited as ATCC
designation number PTA-125691.

[0410] In some embodiments, the mEVs are from Ruminococcus gnavus bacteria. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0411] In some embodiments, the mEVs are from Megasphaera sp. bacteria.
In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770.
In some embodiments, the Megasphaera sp. bacteria are from Megasphaera sp.
bacteria deposited as ATCC designation number PTA-126770.

[0412] In some embodiments, the mEVs are from Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696.

[0413] In some embodiments, the mEVs are from Harryflintia acetispora bacteria.
In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[0414] In some embodiments, the mEVs are from bacteria of the family Acidaminococcaceae, Alcahgenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae.

[0415] In some embodiments, the mEVs are from bacteria of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0416] In some embodiments, the mEVs are from Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium an/malls, or Bifidobacterium breve bacteria.

[0417] In some embodiments, the mEVs are from BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[0418] In some embodiments, the mEVs are from Blautia hydrogenotrophica bacteria.

[0419] In some embodiments, the mEVs are from Blautia stercoris bacteria.

[0420] In some embodiments, the mEVs are from Blautia w exlerae bacteria.

[0421] In some embodiments, the mEVs are from Enterococcus gallinarum bacteria.

[0422] In some embodiments, the mEVs are from Enterococcus faecium bacteria.

[0423] In some embodiments, the mEVs are from Bifidobacterium bifidium bacteria.

[0424] In some embodiments, the mEVs are from Bifidobacterium breve bacteria.

[0425] In some embodiments, the mEVs are from Bifidobacterium longum bacteria.

[0426] In some embodiments, the mEVs are from Roseburia hominis bacteria.

[0427] In some embodiments, the mEVs are from Bacteroides thetaiotaomicron bacteria.

[0428] In some embodiments, the mEVs are from Bacteroides coprocola bacteria.

[0429] In some embodiments, the mEVs are from Erysipelatoclostridium ramosum bacteria.

[0430] In some embodiments, the mEVs are from Megasphera massiliensis bacteria.

[0431] In some embodiments, the mEVs are from Eubacterium bacteria.

[0432] In some embodiments, the mEVs are from Parabacteroides distasonis bacteria.

[0433] In some embodiments, the mEVs are from Lactobacillus plantarum bacteria.

[0434] In some embodiments, the mEVs are from bacteria of the Negativicutes class.

[0435] In some embodiments, the mEVs are from bacteria of the Veillonellaceae family.

[0436] In some embodiments, the mEVs are from bacteria of the Selenomonadaceae family.

[0437] In some embodiments, the mEVs are from bacteria of the Acidaminococcaceae family.

[0438] In some embodiments, the mEVs are from bacteria of the Sporomusaceae family.

[0439] In some embodiments, the mEVs are from bacteria of the Megasphaera genus.

[0440] In some embodiments, the mEVs are from bacteria of the Selenomonas genus.

[0441] In some embodiments, the mEVs are from bacteria of the Propionospora genus.

[0442] In some embodiments, the mEVs are from bacteria of the Acidaminococcus genus.

[0443] In some embodiments, the mEVs are from Megasphaera sp. bacteria.

[0444] In some embodiments, the mEVs are from Selenomonas felix bacteria.

[0445] In some embodiments, the mEVs are from Acidaminococcus intestini bacteria.

[0446] In some embodiments, the mEVs are from Propionospora sp. bacteria.

[0447] In some embodiments, the mEVs are from bacteria of the Clostridia class.

[0448] In some embodiments, the mEVs are from bacteria of the Oscillospriraceae family.

[0449] In some embodiments, the mEVs are from bacteria of the Faecalibacterium genus.

[0450] In some embodiments, the mEVs are from bacteria of the Fournierella genus.

[0451] In some embodiments, the mEVs are from bacteria of the Harryflintia genus.

[0452] In some embodiments, the mEVs are from bacteria of the Agathobaculum genus.

[0453] In some embodiments, the mEVs are from Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[0454] In some embodiments, the mEVs are from Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[0455] In some embodiments, the mEVs are from Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[0456] In some embodiments, the mEVs are from Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[0457] In some embodiments, the mEVs are from a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[0458] In some embodiments, the mEVs are from bacteria of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the mEVs are from bacteria of order Bacteroidales. In some embodiments, the mEVs are from bacteria of the family Porphyromonoadaceae . In some embodiments, the mEVs are from bacteria of the family Prevotellaceae. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Bacteroidia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[0459] In some embodiments, the mEVs are from bacteria of the class Clostridia [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Eubacteriales. In some embodiments, the mEVs are from bacteria of the family Oscillispiraceae. In some embodiments, the mEVs are from bacteria of the family Lachnospiraceae . In some embodiments, the mEVs are from bacteria of the family Peptostreptococcaceae. In some embodiments, the mEVs are from bacteria of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram positive. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[0460] In some embodiments, the mEVs are from bacteria of the class Negativicutes [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Veil/one/la/es. In some embodiments, the mEVs are from bacteria of the family Veillonelloceae. In some embodiments, the mEVs are from bacteria of the order Selenomonadales. In some embodiments, the mEVs are from bacteria of the family Selenomonadaceae. In some embodiments, the mEVs are from bacteria of the family Sporomusaceae. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm.
In some embodiments, the mEVs are from bacteria of the class Negativicutes that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0461] In some embodiments, the mEVs are from bacteria of the class Synergistia [phylum Synergistota]. In some embodiments, the mEVs are from bacteria of the order Synergistales. In some embodiments, the mEVs are from bacteria of the family Synergistaceae. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Synergistia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0462] In some embodiments, the mEVs are from bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[0463] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[0464] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[0465] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[0466] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus

[0467] In some embodiments, the mEVs are from bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[0468] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 107 to about 2 x 10 12 (e.g., about 3 x 1010 or about 1.5 x 1011 or about 1.5 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 1010 to about 2 x 1012 (e.g., about 1.6 x 1011 or about 8 x 1011 or about 9.6 x 1011 about 12.8 x 1011 or about 1.6 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0469] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 109, about 3 x 109, about 5 x 109, about 1.5 x 1010, about 3 x 1010, about 5 x 1010, about 1.5 x 1011, about 1.5 x 1012, or about 2 x 1012 cells, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0470] In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 105 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 1010 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0471] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of drug substance that contains the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 10 mg to about 3500 mg, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0472] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of drug substance that contains the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 30 mg to about1300 mg (by weight of bacteria and/or mEVs) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0473] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 2x106 to about 2x10'6 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0474] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 5 mg to about 900 mg total protein (e.g., wherein total protein is determined by Bradford assay or BCA), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

[0475] In some embodiments, the solid dosage form further comprises one or more additional pharmaceutical agents.

[0476] In some embodiments, the solid dosage form further comprises an excipient (e.g., an excipient described herein, e.g., a diluent, a binder and/or an adhesive, a disintegrant, a lubricant and/or a glidant, a coloring agent, a flavoring agent, and/or a sweetening agent).

[0477] In some aspects, the disclosure provides a method for preparing an enterically coated capsule comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:

[0478] a) loading the pharmaceutical agent into a capsule; and

[0479] b) enterically coating the capsule, thereby preparing the enterically coated capsule.

[0480] In some embodiments, the method comprises combining the pharmaceutical agent with a pharmaceutically acceptable excipient prior to loading into the capsule.

[0481] In some embodiments, the method for preparing an enterically coated capsule comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), comprises:

[0482] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;

[0483] b) loading the pharmaceutical agent and pharmaceutically acceptable excipient into a capsule; and

[0484] c) enterically coating the capsule, thereby preparing the enterically coated capsule.

[0485] In some embodiments, the method further comprises banding the capsule after loading the capsule and prior to enterically coating the capsule. In some embodiments, the capsule is banded with an HPMC-based banding solution.

[0486] In some embodiments, the disclosure provides a method for preparing an enterically coated capsule comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:

[0487] a) loading the pharmaceutical agent into a capsule;

[0488] b) banding the capsule; and

[0489] c) enterically coating the capsule, thereby preparing the enterically coated capsule.

[0490] In some embodiments, the disclosure provides a method for preparing an enterically coated capsule comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:

[0491] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;

[0492] b) loading the pharmaceutical agent and pharmaceutically acceptable excipient into a capsule;

[0493] c) banding the capsule; and

[0494] d) enterically coating the capsule, thereby preparing the enterically coated capsule.

[0495] In certain embodiments, the solid dosage form comprises a capsule.
In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
In some embodiments, the capsule is a size 0 capsule.

[0496] In some embodiments, the capsule comprises HPMC or gelatin. In some embodiments, the capsule comprises HPMC.

[0497] In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not identical (e.g., the inner and outer enteric coatings do not contain identical components in identical amounts).

[0498] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a polymethacrylate-based copolymer.

[0499] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

[0500] In some embodiments, the one enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[0501] In some embodiments, the one enteric coating comprises a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS
30 D).

[0502] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

[0503] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises an anionic polymeric material.

[0504] In some embodiments, the pharmaceutical agent comprises bacteria.

[0505] In some embodiments, the pharmaceutical agent comprises microbial extracellular vesicles (mEV).

[0506] In some embodiments, the pharmaceutical agent comprises bacteria and microbial extracellular vesicles (mEV).

[0507] In some embodiments, the pharmaceutical agent has one or more beneficial immune effects outside the gastrointestinal tract, e.g., when the solid dosage form is orally administered.

[0508] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract (e.g., outside of the small intestine) in the subject, e.g., when the solid dosage form is orally administered.

[0509] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[0510] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine (e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinsl tract), e.g., when the solid dosage form is orally administered.

[0511] In some embodiments, the pharmaceutical agent comprises isolated bacteria (e.g., from one or more strains of bacteria (e.g., bacteria of interest) (e.g., a therapeutically effective amount thereof)). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is the isolated bacteria (e.g., bacteria of interest).

[0512] In some embodiments, the pharmaceutical agent comprises bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

[0513] In some embodiments, the pharmaceutical agent comprises live bacteria.

[0514] In some embodiments, the pharmaceutical agent comprises dead bacteria.

[0515] In some embodiments, the pharmaceutical agent comprises non-replicating bacteria.

[0516] In some embodiments, the pharmaceutical agent comprises bacteria from one strain of microbe (e.g., bacteria).

[0517] In some embodiments, the bacteria are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient) (e.g., a powder form).

[0518] In some embodiments, the bacteria are gamma irradiated.

[0519] In some embodiments, the bacteria are UV irradiated.

[0520] In some embodiments, the bacteria are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).

[0521] In some embodiments, the bacteria are acid treated.

[0522] In some embodiments, the bacteria are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0523] In some embodiments, the bacteria are Gram positive bacteria.

[0524] In some embodiments, the bacteria are Gram negative bacteria.

[0525] In some embodiments, the bacteria are aerobic bacteria.

[0526] In some embodiments, the bacteria are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0527] In some embodiments, the bacteria are acidophile bacteria.

[0528] In some embodiments, the bacteria are alkaliphile bacteria.

[0529] In some embodiments, the bacteria are neutralophile bacteria.

[0530] In some embodiments, the bacteria are fastidious bacteria.

[0531] In some embodiments, the bacteria are nonfastidious bacteria.

[0532] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0533] In some embodiments, the bacteria are a bacterial strain listed in Table 1, Table 2, or Table 3.

[0534] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0535] In some embodiments, the bacteria are a bacterial strain listed in Table J.

[0536] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0537] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae.

[0538] In some embodiments, the bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0539] In some embodiments, the bacteria are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0540] In some embodiments, the bacteria are of the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

[0541] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.

[0542] In some embodiments, the bacteria are Prevotella histicola bacteria.

[0543] In some embodiments, the bacteria are Bifidobacterium animalis bacteria.

[0544] In some embodiments, the bacteria are Veillonella parvula bacteria.

[0545] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.
In some embodiments, the Lactococcus lactis cremoris bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0546] In some embodiments, the bacteria are Prevotella bacteria. In some embodiments, the Prevotella bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are Prevotella Strain B 50329 (NRRL accession number B 50329).

[0547] In some embodiments, the bacteria are Bifidobacterium bacteria. In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are Bifidobacterium bacteria deposited as ATCC
designation number PTA-125097.

[0548] In some embodiments, the bacteria are Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 99%
genomic, 16S
and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are Veil/one/la bacteria deposited as ATCC designation number PTA-125691.

[0549] In some embodiments, the bacteria are from Ruminococcus gnavus bacteria.
In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0550] In some embodiments, the bacteria are Megasphaera sp. bacteria. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are Megasphaera sp. bacteria deposited as ATCC
designation number PTA-126770.

[0551] In some embodiments, the bacteria are Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696.

[0552] In some embodiments, the bacteria are Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[0553] In some embodiments, the bacteria are of the family Acidaminococcaceae, Alcaligenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae .

[0554] In some embodiments, the bacteria are of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0555] In some embodiments, the bacteria are Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium animalis, or Bifidobacterium breve bacteria.

[0556] In some embodiments, the bacteria are BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[0557] In some embodiments, the bacteria are Blautia hydrogenotrophica bacteria.

[0558] In some embodiments, the bacteria are Blautia stercoris bacteria.

[0559] In some embodiments, the bacteria are Blautia w exlerae bacteria.

[0560] In some embodiments, the bacteria are Enterococcus galhnarum bacteria.

[0561] In some embodiments, the bacteria are Enterococcus faecium bacteria.

[0562] In some embodiments, the bacteria are Bifidobacterium bifidium bacteria.

[0563] In some embodiments, the bacteria are Bifidobacterium breve bacteria.

[0564] In some embodiments, the bacteria are Bifidobacterium longum bacteria.

[0565] In some embodiments, the bacteria are Roseburia hominis bacteria.

[0566] In some embodiments, the bacteria are Bacteroides thetaiotaomicron bacteria.

[0567] In some embodiments, the bacteria are Bacteroides coprocola bacteria.

[0568] In some embodiments, the bacteria are Erysipelatoclostridium ramosum bacteria.

[0569] In some embodiments, the bacteria are Megasphera massiliensis bacteria.

[0570] In some embodiments, the bacteria are Eubacterium bacteria.

[0571] In some embodiments, the bacteria are Parabacteroides distasonis bacteria.

[0572] In some embodiments, the bacteria are Lactobacillus plantarum bacteria.

[0573] In some embodiments, the bacteria are bacteria of the Negativicutes class.

[0574] In some embodiments, the bacteria are of the Veillonellaceae family.

[0575] In some embodiments, the bacteria are of the Selenomonadaceae family.

[0576] In some embodiments, the bacteria are of the Acidaminococcaceae family.

[0577] In some embodiments, the bacteria are of the Sporomusaceae family.

[0578] In some embodiments, the bacteria are of the Megasphaera genus.

[0579] In some embodiments, the bacteria are of the Selenomonas genus.

[0580] In some embodiments, the bacteria are of the Propionospora genus.

[0581] In some embodiments, the bacteria are of the Acidaminococcus genus.

[0582] In some embodiments, the bacteria are Megasphaera sp. bacteria.

[0583] In some embodiments, the bacteria are Selenomonas felix bacteria.

[0584] In some embodiments, the bacteria are Acidaminococcus intestini bacteria.

[0585] In some embodiments, the bacteria are Propionospora sp. bacteria.

[0586] In some embodiments, the bacteria are bacteria of the Clostridia class.

[0587] In some embodiments, the bacteria are of the Oscillospriraceae family.

[0588] In some embodiments, the bacteria are of the Faecalibacterium genus.

[0589] In some embodiments, the bacteria are of the Fournierella genus.

[0590] In some embodiments, the bacteria are of the Harryflintia genus.

[0591] In some embodiments, the bacteria are of the Agathobaculum genus.

[0592] In some embodiments, the bacteria are Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[0593] In some embodiments, the bacteria are Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[0594] In some embodiments, the bacteria are Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[0595] In some embodiments, the bacteria are Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[0596] In some embodiments, the bacteria are a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[0597] In some embodiments, the bacteria are of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the bacteria are of order Bacteroidales.
In some embodiments, the bacteria are of the family Porphyromonoadaceae . In some embodiments, the bacteria are of the family Prevotellaceae . In some embodiments, the bacteria are of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Bacteroidia that stain Gram negative. In some embodiments, the bacteria are of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[0598] In some embodiments, the bacteria are of the class Clostridia [phylum Firmicutes]. In some embodiments, the bacteria are of the order Eubacteriales.
In some embodiments, the bacteria are of the family Oscillispiraceae. In some embodiments, the bacteria are of the family Lachnospiraceae. In some embodiments, the bacteria are of the family Peptostreptococcaceae. In some embodiments, the bacteria are of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the bacteria are of the class Clostridia that stain Gram negative. In some embodiments, the bacteria are of the class Clostridia that stain Gram positive. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[0599] In some embodiments, the bacteria are of the class Negativicutes [phylum Firmicutes]. In some embodiments, the bacteria are of the order Veillonellales. In some embodiments, the bacteria are of the family Veillonelloceae. In some embodiments, the bacteria are of the order Selenomonadales. In some embodiments, the bacteria are of the family Selenomonadaceae. In some embodiments, the bacteria are of the family Sporomusaceae. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Negativicutes that stain Gram negative. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0600] In some embodiments, the bacteria are of the class Synergistia [phylum Synergistota]. In some embodiments, the bacteria are of the order Synergi stales. In some embodiments, the bacteria are of the family Synergistaceae. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Synergistia that stain Gram negative. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0601] In some embodiments, the bacteria are bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[0602] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[0603] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[0604] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[0605] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[0606] In some embodiments, the bacteria are bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[0607] In some embodiments, the pharmaceutical agent comprises isolated mEVs (e.g., from one or more strains of bacteria (e.g., bacteria of interest)) (e.g., a therapeutically effective amount thereof). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is isolated mEV of bacteria (e.g., bacteria of interest).

[0608] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise secreted mEVs (smEVs).

[0609] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise processed mEVs (pmEVs).

[0610] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from bacteria that have been gamma irradiated, UV
irradiated, heat inactivated, acid treated, or oxygen sparged.

[0611] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from live bacteria.

[0612] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from dead bacteria.

[0613] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from non-replicating bacteria.

[0614] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs are from one strain of bacteria.

[0615] In some embodiments, the mEVs are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient).

[0616] In some embodiments, the mEVs are gamma irradiated.

[0617] In some embodiments, the mEVs are UV irradiated.

[0618] In some embodiments, the mEVs are heat inactivated (e.g., at 50 C
for two hours or at 90 C for two hours).

[0619] In some embodiments, the mEVs are acid treated.

[0620] In some embodiments, the mEVs are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0621] In some embodiments, the mEVs are from Gram positive bacteria.

[0622] In some embodiments, the mEVs are from Gram negative bacteria.

[0623] In some embodiments, the mEVs are from aerobic bacteria.

[0624] In some embodiments, the mEVs are from anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0625] In some embodiments, the mEVs are from acidophile bacteria.

[0626] In some embodiments, the mEVs are from alkaliphile bacteria.

[0627] In some embodiments, the mEVs are from neutralophile bacteria.

[0628] In some embodiments, the mEVs are from fastidious bacteria.

[0629] In some embodiments, the mEVs are from nonfastidious bacteria.

[0630] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0631] In some embodiments, the bacteria are a bacterial strain listed in Table 1, Table 2, or Table 3.

[0632] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0633] In some embodiments, the bacteria are a bacterial strain listed in Table J.

[0634] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0635] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae.

[0636] In some embodiments, the mEVs are from bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0637] In some embodiments, the mEVs are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0638] In some embodiments, the mEVs are from bacteria of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one//a.

[0639] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria.

[0640] In some embodiments, the mEVs are from Prevotella histicola bacteria.

[0641] In some embodiments, the mEVs are from Bifidobacterium animalis bacteria.

[0642] In some embodiments, the mEVs are from Veil/one/la parvula bacteria.

[0643] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria. In some embodiments, the Lactococcus lactis cremoris bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0644] In some embodiments, the mEVs are from Prevotella bacteria. In some embodiments, the Prevotella bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are from a strain comprising at least 99% genomic, 16S
and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are from Prevotella Strain B 50329 (NRRL accession number B 50329).

[0645] In some embodiments, the mEVs are from Bifidobacterium bacteria.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are from Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.

[0646] In some embodiments, the mEVs are from Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from Veil/one/la bacteria deposited as ATCC
designation number PTA-125691.

[0647] In some embodiments, the mEVs are from Ruminococcus gnavus bacteria. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0648] In some embodiments, the mEVs are from Megasphaera sp. bacteria.
In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770.
In some embodiments, the Megasphaera sp. bacteria are from Megasphaera sp.
bacteria deposited as ATCC designation number PTA-126770.

[0649] In some embodiments, the mEVs are from Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696.

[0650] In some embodiments, the mEVs are from Harryflintia acetispora bacteria.
In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[0651] In some embodiments, the mEVs are from bacteria of the family Acidaminococcaceae, Alcahgenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae.

[0652] In some embodiments, the mEVs are from bacteria of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0653] In some embodiments, the mEVs are from Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium an/malls, or Bifidobacterium breve bacteria.

[0654] In some embodiments, the mEVs are from BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[0655] In some embodiments, the mEVs are from Blautia hydrogenotrophica bacteria.

[0656] In some embodiments, the mEVs are from Blautia stercoris bacteria.

[0657] In some embodiments, the mEVs are from Blautia w exlerae bacteria.

[0658] In some embodiments, the mEVs are from Enterococcus gallinarum bacteria.

[0659] In some embodiments, the mEVs are from Enterococcus faecium bacteria.

[0660] In some embodiments, the mEVs are from Bifidobacterium bifidium bacteria.

[0661] In some embodiments, the mEVs are from Bifidobacterium breve bacteria.

[0662] In some embodiments, the mEVs are from Bifidobacterium longum bacteria.

[0663] In some embodiments, the mEVs are from Roseburia hominis bacteria.

[0664] In some embodiments, the mEVs are from Bacteroides thetaiotaomicron bacteria.

[0665] In some embodiments, the mEVs are from Bacteroides coprocola bacteria.

[0666] In some embodiments, the mEVs are from Erysipelatoclostridium ramosum bacteria.

[0667] In some embodiments, the mEVs are from Megasphera massiliensis bacteria.

[0668] In some embodiments, the mEVs are from Eubacterium bacteria.

[0669] In some embodiments, the mEVs are from Parabacteroides distasonis bacteria.

[0670] In some embodiments, the mEVs are from Lactobacillus plantarum bacteria.

[0671] In some embodiments, the mEVs are from bacteria of the Negativicutes class.

[0672] In some embodiments, the mEVs are from bacteria of the Veillonellaceae family.

[0673] In some embodiments, the mEVs are from bacteria of the Selenomonadaceae family.

[0674] In some embodiments, the mEVs are from bacteria of the Acidaminococcaceae family.

[0675] In some embodiments, the mEVs are from bacteria of the Sporomusaceae family.

[0676] In some embodiments, the mEVs are from bacteria of the Megasphaera genus.

[0677] In some embodiments, the mEVs are from bacteria of the Selenomonas genus.

[0678] In some embodiments, the mEVs are from bacteria of the Propionospora genus.

[0679] In some embodiments, the mEVs are from bacteria of the Acidaminococcus genus.

[0680] In some embodiments, the mEVs are from Megasphaera sp. bacteria.

[0681] In some embodiments, the mEVs are from Selenomonas felix bacteria.

[0682] In some embodiments, the mEVs are from Acidaminococcus intestini bacteria.

[0683] In some embodiments, the mEVs are from Propionospora sp. bacteria.

[0684] In some embodiments, the mEVs are from bacteria of the Clostridia class.

[0685] In some embodiments, the mEVs are from bacteria of the Oscillospriraceae family.

[0686] In some embodiments, the mEVs are from bacteria of the Faecalibacterium genus.

[0687] In some embodiments, the mEVs are from bacteria of the Fournierella genus.

[0688] In some embodiments, the mEVs are from bacteria of the Harryflintia genus.

[0689] In some embodiments, the mEVs are from bacteria of the Agathobaculum genus.

[0690] In some embodiments, the mEVs are from Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[0691] In some embodiments, the mEVs are from Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[0692] In some embodiments, the mEVs are from Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[0693] In some embodiments, the mEVs are from Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[0694] In some embodiments, the mEVs are from a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[0695] In some embodiments, the mEVs are from bacteria of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the mEVs are from bacteria of order Bacteroidales. In some embodiments, the mEVs are from bacteria of the family Porphyromonoadaceae . In some embodiments, the mEVs are from bacteria of the family Prevotellaceae. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Bacteroidia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[0696] In some embodiments, the mEVs are from bacteria of the class Clostridia [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Eubacteriales. In some embodiments, the mEVs are from bacteria of the family Oscillispiraceae. In some embodiments, the mEVs are from bacteria of the family Lachnospiraceae . In some embodiments, the mEVs are from bacteria of the family Peptostreptococcaceae. In some embodiments, the mEVs are from bacteria of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram positive. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[0697] In some embodiments, the mEVs are from bacteria of the class Negativicutes [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Veil/one/la/es. In some embodiments, the mEVs are from bacteria of the family Veillonelloceae. In some embodiments, the mEVs are from bacteria of the order Selenomonadales. In some embodiments, the mEVs are from bacteria of the family Selenomonadaceae. In some embodiments, the mEVs are from bacteria of the family Sporomusaceae. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm.
In some embodiments, the mEVs are from bacteria of the class Negativicutes that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0698] In some embodiments, the mEVs are from bacteria of the class Synergistia [phylum Synergistota]. In some embodiments, the mEVs are from bacteria of the order Synergistales. In some embodiments, the mEVs are from bacteria of the family Synergistaceae. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Synergistia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0699] In some embodiments, the mEVs are from bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[0700] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[0701] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[0702] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[0703] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus

[0704] In some embodiments, the mEVs are from bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[0705] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 107 to about 2 x 1012 (e.g., about 3 x 1010 or about 1.5 x 1011 or about 1.5 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule. In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 1010 to about 2 x 1012 (e.g., about 1.6 x 1011 or about 8 x 1011 or about 9.6 x 1011 about 12.8 x 1011 or about 1.6 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule.

[0706] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 109, about 3 x 109, about 5 x 109, about 1.5 x 1010, about 3 x 1010, about 5 x 1010, about 1.5 x 1011, about 1.5 x 1012, or about 2 x 1012 cells, wherein the dose is per capsule.

[0707] In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 105 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 1010 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule.

[0708] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 10 mg to about 3500 mg, wherein the dose is per tablet.

[0709] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of drug substance that contains the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 30 mg to about1300 mg (by weight of bacteria and/or mEVs) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg, wherein the dose is per capsule.

[0710] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 2x106 to about 2x10'6 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule.

[0711] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 5 mg to about 900 mg total protein (e.g., wherein total protein is determined by Bradford assay or BCA), wherein the dose is per capsule.

[0712] In some embodiments, the can be (or be present in) a medicinal product, medical food, a food product, or a dietary supplement.

[0713] In some embodiments, the solid dosage form further comprises one or more additional pharmaceutical agents.

[0714] In some embodiments, the solid dosage form further comprises an excipient (e.g., an excipient described herein, e.g., a diluent, a binder and/or an adhesive, a disintegrant, a lubricant and/or a glidant, a coloring agent, a flavoring agent, and/or a sweetening agent).

[0715] In some aspects, the disclosure provides a method for preparing an enterically coated tablet comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:

[0716] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;

[0717] b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a tablet; and

[0718] c) enterically coating the tablet, thereby preparing the enterically coated tablet.

[0719] In some embodiments, the tablet (e.g., enterically coated tablet) is a 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 1 lmm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, or 18mm tablet.

[0720] In some embodiments, the enteric coating comprises one enteric coating.

[0721] In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not identical (e.g., the inner and outer enteric coatings do not contain identical components in identical amounts).

[0722] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a polymethacrylate-based copolymer.

[0723] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

[0724] In some embodiments, the one enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[0725] In some embodiments, the one enteric coating comprises a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS
30 D).

[0726] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

[0727] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises an anionic polymeric material.

[0728] In some embodiments, the pharmaceutical agent comprises bacteria.

[0729] In some embodiments, the pharmaceutical agent comprises microbial extracellular vesicles (mEV).

[0730] In some embodiments, the pharmaceutical agent comprises bacteria and microbial extracellular vesicles (mEV).

[0731] In some embodiments, the pharmaceutical agent has one or more beneficial immune effects outside the gastrointestinal tract, e.g., when the solid dosage form is orally administered.

[0732] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract (e.g., outside of the small intestine) in the subject, e.g., when the solid dosage form is orally administered.

[0733] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[0734] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine (e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinsl tract), e.g., when the solid dosage form is orally administered.

[0735] In some embodiments, the pharmaceutical agent comprises isolated bacteria (e.g., from one or more strains of bacteria (e.g., bacteria of interest) (e.g., a therapeutically effective amount thereof)). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is the isolated bacteria (e.g., bacteria of interest).

[0736] In some embodiments, the pharmaceutical agent comprises bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

[0737] In some embodiments, the pharmaceutical agent comprises live bacteria.

[0738] In some embodiments, the pharmaceutical agent comprises dead bacteria.

[0739] In some embodiments, the pharmaceutical agent comprises non-replicating bacteria.

[0740] In some embodiments, the pharmaceutical agent comprises bacteria from one strain of microbe (e.g., bacteria).

[0741] In some embodiments, the bacteria are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient) (e.g., a powder form).

[0742] In some embodiments, the bacteria are gamma irradiated.

[0743] In some embodiments, the bacteria are UV irradiated.

[0744] In some embodiments, the bacteria are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).

[0745] In some embodiments, the bacteria are acid treated.

[0746] In some embodiments, the bacteria are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0747] In some embodiments, the bacteria are Gram positive bacteria.

[0748] In some embodiments, the bacteria are Gram negative bacteria.

[0749] In some embodiments, the bacteria are aerobic bacteria.

[0750] In some embodiments, the bacteria are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0751] In some embodiments, the bacteria are acidophile bacteria.

[0752] In some embodiments, the bacteria are alkaliphile bacteria.

[0753] In some embodiments, the bacteria are neutralophile bacteria.

[0754] In some embodiments, the bacteria are fastidious bacteria.

[0755] In some embodiments, the bacteria are nonfastidious bacteria.

[0756] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0757] In some embodiments, the bacteria are a bacterial strain listed in Table 1, Table 2, or Table 3.

[0758] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0759] In some embodiments, the bacteria are a bacterial strain listed in Table J.

[0760] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0761] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae.

[0762] In some embodiments, the bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0763] In some embodiments, the bacteria are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0764] In some embodiments, the bacteria are of the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

[0765] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.

[0766] In some embodiments, the bacteria are Prevotella histicola bacteria.

[0767] In some embodiments, the bacteria are Bifidobacterium animalis bacteria.

[0768] In some embodiments, the bacteria are Veil/one/la parvula bacteria.

[0769] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.
In some embodiments, the Lactococcus lactis cremoris bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0770] In some embodiments, the bacteria are Prevotella bacteria. In some embodiments, the Prevotella bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are Prevotella Strain B 50329 (NRRL accession number B 50329).

[0771] In some embodiments, the bacteria are Bifidobacterium bacteria. In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are Bifidobacterium bacteria deposited as ATCC
designation number PTA-125097.

[0772] In some embodiments, the bacteria are Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 99%
genomic, 16S
and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are Veil/one/la bacteria deposited as ATCC designation number PTA-125691.

[0773] In some embodiments, the bacteria are from Ruminococcus gnavus bacteria.
In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0774] In some embodiments, the bacteria are Megasphaera sp. bacteria. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are Megasphaera sp. bacteria deposited as ATCC
designation number PTA-126770.

[0775] In some embodiments, the bacteria are Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696.

[0776] In some embodiments, the bacteria are Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[0777] In some embodiments, the bacteria are of the family Acidaminococcaceae, Alcaligenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae.

[0778] In some embodiments, the bacteria are of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0779] In some embodiments, the bacteria are Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium animalis, or Bifidobacterium breve bacteria.

[0780] In some embodiments, the bacteria are BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholderia, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[0781] In some embodiments, the bacteria are Blautia hydrogenotrophica bacteria.

[0782] In some embodiments, the bacteria are Blautia stercoris bacteria.

[0783] In some embodiments, the bacteria are Blautia w exlerae bacteria.

[0784] In some embodiments, the bacteria are Enterococcus gallinarum bacteria.

[0785] In some embodiments, the bacteria are Enterococcus faecium bacteria.

[0786] In some embodiments, the bacteria are Bifidobacterium bifidium bacteria.

[0787] In some embodiments, the bacteria are Bifidobacterium breve bacteria.

[0788] In some embodiments, the bacteria are Bifidobacterium longum bacteria.

[0789] In some embodiments, the bacteria are Roseburia hominis bacteria.

[0790] In some embodiments, the bacteria are Bacteroides thetaiotaomicron bacteria.

[0791] In some embodiments, the bacteria are Bacteroides coprocola bacteria.

[0792] In some embodiments, the bacteria are Erysipelatoclostridium ramosum bacteria.

[0793] In some embodiments, the bacteria are Megasphera massiliensis bacteria.

[0794] In some embodiments, the bacteria are Eubacterium bacteria.

[0795] In some embodiments, the bacteria are Parabacteroides distasonis bacteria.

[0796] In some embodiments, the bacteria are Lactobacillus plantarum bacteria.

[0797] In some embodiments, the bacteria are bacteria of the Negativicutes class.

[0798] In some embodiments, the bacteria are of the Veillonellaceae family.

[0799] In some embodiments, the bacteria are of the Selenomonadaceae family.

[0800] In some embodiments, the bacteria are of the Acidaminococcaceae family.

[0801] In some embodiments, the bacteria are of the Sporomusaceae family.

[0802] In some embodiments, the bacteria are of the Megasphaera genus.

[0803] In some embodiments, the bacteria are of the Selenomonas genus.

[0804] In some embodiments, the bacteria are of the Propionospora genus.

[0805] In some embodiments, the bacteria are of the Acidaminococcus genus.

[0806] In some embodiments, the bacteria are Megasphaera sp. bacteria.

[0807] In some embodiments, the bacteria are Selenomonas felix bacteria.

[0808] In some embodiments, the bacteria are Acidaminococcus intestini bacteria.

[0809] In some embodiments, the bacteria are Propionospora sp. bacteria.

[0810] In some embodiments, the bacteria are bacteria of the Clostridia class.

[0811] In some embodiments, the bacteria are of the Oscillospriraceae family.

[0812] In some embodiments, the bacteria are of the Faecalibacterium genus.

[0813] In some embodiments, the bacteria are of the Fournierella genus.

[0814] In some embodiments, the bacteria are of the Harryflintia genus.

[0815] In some embodiments, the bacteria are of the Agathobaculum genus.

[0816] In some embodiments, the bacteria are Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[0817] In some embodiments, the bacteria are Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[0818] In some embodiments, the bacteria are Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[0819] In some embodiments, the bacteria are Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[0820] In some embodiments, the bacteria are a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[0821] In some embodiments, the bacteria are of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the bacteria are of order Bacteroidales .
In some embodiments, the bacteria are of the family Porphyromonoadaceae . In some embodiments, the bacteria are of the family Prevotellaceae . In some embodiments, the bacteria are of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Bacteroidia that stain Gram negative. In some embodiments, the bacteria are of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[0822] In some embodiments, the bacteria are of the class Clostridia [phylum Firmicutes]. In some embodiments, the bacteria are of the order Eubacteriales.
In some embodiments, the bacteria are of the family Oscillispiraceae . In some embodiments, the bacteria are of the family Lachnospiraceae . In some embodiments, the bacteria are of the family Peptostreptococcaceae. In some embodiments, the bacteria are of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the bacteria are of the class Clostridia that stain Gram negative. In some embodiments, the bacteria are of the class Clostridia that stain Gram positive. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[0823] In some embodiments, the bacteria are of the class Negativicutes [phylum Firmicutes]. In some embodiments, the bacteria are of the order Veillonellales. In some embodiments, the bacteria are of the family Veillonelloceae. In some embodiments, the bacteria are of the order Selenomonadales. In some embodiments, the bacteria are of the family Selenomonadaceae. In some embodiments, the bacteria are of the family Sporomusaceae. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Negativicutes that stain Gram negative. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0824] In some embodiments, the bacteria are of the class Synergistia [phylum Synergistota]. In some embodiments, the bacteria are of the order Synergistales. In some embodiments, the bacteria are of the family Synergistaceae. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Synergistia that stain Gram negative. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0825] In some embodiments, the bacteria are bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[0826] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[0827] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[0828] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[0829] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[0830] In some embodiments, the bacteria are bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[0831]

[0832] In some embodiments, the pharmaceutical agent comprises isolated mEVs (e.g., from one or more strains of bacteria (e.g., bacteria of interest)) (e.g., a therapeutically effective amount thereof). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is isolated mEV of bacteria (e.g., bacteria of interest).

[0833] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise secreted mEVs (smEVs).

[0834] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise processed mEVs (pmEVs).

[0835] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from bacteria that have been gamma irradiated, UV
irradiated, heat inactivated, acid treated, or oxygen sparged.

[0836] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from live bacteria.

[0837] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from dead bacteria.

[0838] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from non-replicating bacteria.

[0839] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs are from one strain of bacteria.

[0840] In some embodiments, the mEVs are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient).

[0841] In some embodiments, the mEVs are gamma irradiated.

[0842] In some embodiments, the mEVs are UV irradiated.

[0843] In some embodiments, the mEVs are heat inactivated (e.g., at 50 C
for two hours or at 90 C for two hours).

[0844] In some embodiments, the mEVs are acid treated.

[0845] In some embodiments, the mEVs are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0846] In some embodiments, the mEVs are from Gram positive bacteria.

[0847] In some embodiments, the mEVs are from Gram negative bacteria.

[0848] In some embodiments, the mEVs are from aerobic bacteria.

[0849] In some embodiments, the mEVs are from anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0850] In some embodiments, the mEVs are from acidophile bacteria.

[0851] In some embodiments, the mEVs are from alkaliphile bacteria.

[0852] In some embodiments, the mEVs are from neutralophile bacteria.

[0853] In some embodiments, the mEVs are from fastidious bacteria.

[0854] In some embodiments, the mEVs are from nonfastidious bacteria.

[0855] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0856] In some embodiments, the mEVs are from a bacterial strain listed in Table 1, Table 2, or Table 3.

[0857] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0858] In some embodiments, the mEVs are from a bacterial strain listed in Table J.

[0859] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0860] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae.

[0861] In some embodiments, the mEVs are from bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0862] In some embodiments, the mEVs are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0863] In some embodiments, the mEVs are from bacteria of the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

[0864] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria.

[0865] In some embodiments, the mEVs are from Prevotella histicola bacteria.

[0866] In some embodiments, the mEVs are from Bifidobacterium animalis bacteria.

[0867] In some embodiments, the mEVs are from Veil/one/la parvula bacteria.

[0868] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria. In some embodiments, the Lactococcus lactis cremoris bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0869] In some embodiments, the mEVs are from Prevotella bacteria. In some embodiments, the Prevotella bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are from a strain comprising at least 99% genomic, 16S
and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are from Prevotella Strain B 50329 (NRRL accession number B 50329).

[0870] In some embodiments, the mEVs are from Bifidobacterium bacteria.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are from Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.

[0871] In some embodiments, the mEVs are from Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from Veil/one/la bacteria deposited as ATCC
designation number PTA-125691.

[0872] In some embodiments, the mEVs are from Ruminococcus gnavus bacteria. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0873] In some embodiments, the mEVs are from Megasphaera sp. bacteria.
In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770.
In some embodiments, the Megasphaera sp. bacteria are from Megasphaera sp.
bacteria deposited as ATCC designation number PTA-126770.

[0874] In some embodiments, the mEVs are from Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC

designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696.

[0875] In some embodiments, the mEVs are from Harryflintia acetispora bacteria.
In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[0876] In some embodiments, the mEVs are from bacteria of the family Acidaminococcaceae, Alcahgenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae.

[0877] In some embodiments, the mEVs are from bacteria of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0878] In some embodiments, the mEVs are from Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus galhnarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium animalis, or Bifidobacterium breve bacteria.

[0879] In some embodiments, the mEVs are from BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholderia, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[0880] In some embodiments, the mEVs are from Blautia hydrogenotrophica bacteria.

[0881] In some embodiments, the mEVs are from Blautia stercoris bacteria.

[0882] In some embodiments, the mEVs are from Blautia wexlerae bacteria.

[0883] In some embodiments, the mEVs are from Enterococcus gallinarum bacteria.

[0884] In some embodiments, the mEVs are from Enterococcus faecium bacteria.

[0885] In some embodiments, the mEVs are from Bifidobacterium bifidium bacteria.

[0886] In some embodiments, the mEVs are from Bifidobacterium breve bacteria.

[0887] In some embodiments, the mEVs are from Bifidobacterium longum bacteria.

[0888] In some embodiments, the mEVs are from Roseburia hominis bacteria.

[0889] In some embodiments, the mEVs are from Bacteroides thetaiotaomicron bacteria.

[0890] In some embodiments, the mEVs are from Bacteroides coprocola bacteria.

[0891] In some embodiments, the mEVs are from Erysipelatoclostridium ramosum bacteria.

[0892] In some embodiments, the mEVs are from Megasphera massiliensis bacteria.

[0893] In some embodiments, the mEVs are from Eubacterium bacteria.

[0894] In some embodiments, the mEVs are from Parabacteroides distasonis bacteria.

[0895] In some embodiments, the mEVs are from Lactobacillus plantarum bacteria.

[0896] In some embodiments, the mEVs are from bacteria of the Negativicutes class.

[0897] In some embodiments, the mEVs are from bacteria of the Veillonellaceae family.

[0898] In some embodiments, the mEVs are from bacteria of the Selenomonadaceae family.

[0899] In some embodiments, the mEVs are from bacteria of the Acidaminococcaceae family.

[0900] In some embodiments, the mEVs are from bacteria of the Sporomusaceae family.

[0901] In some embodiments, the mEVs are from bacteria of the Megasphaera genus.

[0902] In some embodiments, the mEVs are from bacteria of the Selenomonas genus.

[0903] In some embodiments, the mEVs are from bacteria of the Propionospora genus.

[0904] In some embodiments, the mEVs are from bacteria of the Acidaminococcus genus.

[0905] In some embodiments, the mEVs are from Megasphaera sp. bacteria.

[0906] In some embodiments, the mEVs are from Selenomonas felix bacteria.

[0907] In some embodiments, the mEVs are from Acidaminococcus intestini bacteria.

[0908] In some embodiments, the mEVs are from Propionospora sp. bacteria.

[0909] In some embodiments, the mEVs are from bacteria of the Clostridia class.

[0910] In some embodiments, the mEVs are from bacteria of the Oscillospriraceae family.

[0911] In some embodiments, the mEVs are from bacteria of the Faecalibacterium genus.

[0912] In some embodiments, the mEVs are from bacteria of the Fournierella genus.

[0913] In some embodiments, the mEVs are from bacteria of the Harryflintia genus.

[0914] In some embodiments, the mEVs are from bacteria of the Agathobaculum genus.

[0915] In some embodiments, the mEVs are from Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[0916] In some embodiments, the mEVs are from Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[0917] In some embodiments, the mEVs are from Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[0918] In some embodiments, the mEVs are from Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[0919] In some embodiments, the mEVs are from a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[0920] In some embodiments, the mEVs are from bacteria of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the mEVs are from bacteria of order Bacteroidales. In some embodiments, the mEVs are from bacteria of the family Porphyromonoadaceae. In some embodiments, the mEVs are from bacteria of the family Prevotellaceae. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Bacteroidia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[0921] In some embodiments, the mEVs are from bacteria of the class Clostridia [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Eubacteriales. In some embodiments, the mEVs are from bacteria of the family Oscillispiraceae. In some embodiments, the mEVs are from bacteria of the family Lachnospiraceae. In some embodiments, the mEVs are from bacteria of the family Peptostreptococcaceae. In some embodiments, the mEVs are from bacteria of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram positive. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[0922] In some embodiments, the mEVs are from bacteria of the class Negativicutes [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Veil/one/la/es. In some embodiments, the mEVs are from bacteria of the family Veillonelloceae. In some embodiments, the mEVs are from bacteria of the order Selenomonadales. In some embodiments, the mEVs are from bacteria of the family Selenomonadaceae. In some embodiments, the mEVs are from bacteria of the family Sporomusaceae. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm.
In some embodiments, the mEVs are from bacteria of the class Negativicutes that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0923] In some embodiments, the mEVs are from bacteria of the class Synergistia [phylum Synergistota]. In some embodiments, the mEVs are from bacteria of the order Synergistales. In some embodiments, the mEVs are from bacteria of the family Synergistaceae. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Synergistia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[0924] In some embodiments, the mEVs are from bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[0925] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[0926] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[0927] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[0928] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus

[0929] In some embodiments, the mEVs are from bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[0930] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 107 to about 2 x 1012 (e.g., about 3 x 1010 or about 1.5 x 1011 or about 1.5 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per tablet. In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 1010 to about 2 x 1012 (e.g., about 1.6 x 1011 or about 8 x 1011 or about 9.6 x 1011 about 12.8 x 1011 or about 1.6 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per tablet.

[0931] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 109, about 3 x 109, about 5 x 109, about 1.5 x 1010, about 3 x 1010, about 5 x 1010, about 1.5 x 1011, about 1.5 x 1012, or about 2 x 1012 cells, wherein the dose is per tablet.

[0932] In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 105 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 1010 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per tablet.

[0933] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 10 mg to about 3500 mg, wherein the dose is per tablet.

[0934] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of drug substance that contains the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 30 mg to about1300 mg (by weight of bacteria and/or mEVs) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg, wherein the dose is per tablet.

[0935] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 2x106 to about 2x10'6 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per tablet.

[0936] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 5 mg to about 900 mg total protein (e.g., wherein total protein is determined by Bradford assay or BCA), wherein the dose is per tablet.

[0937] In some embodiments, the can be (or be present in) a medicinal product, medical food, a food product, or a dietary supplement.

[0938] In some embodiments, the solid dosage form further comprises one or more additional pharmaceutical agents.
In some embodiments, the solid dosage form further comprises an excipient (e.g., an excipient described herein, e.g., a diluent, a binder and/or an adhesive, a disintegrant, a lubricant and/or a glidant, a coloring agent, a flavoring agent, and/or a sweetening agent).

[0939] In some aspects, the disclosure provides a method for preparing an enterically coated minitablet comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:

[0940] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;

[0941] b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a minitablet; and

[0942] c) enterically coating the minitablet, thereby preparing the enterically coated minitablet.

[0943] In some embodiments, one or more minitablets are loaded into a capsule. In some embodiments, the method further comprises banding the capsule after loading the capsule. In some embodiments, the capsule is banded with an HPMC-based banding solution.

[0944] In some embodiments, the minitablet (e.g., enterically coated minitablet) is a lmm minitablet, 1.5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet.
In some embodiments, a plurality of enterically coated minitablets are contained in a capsule (e.g., a size 0 capsule can contain about 31 to about 35 (e.g., 33) minitablets, wherein the minitablets are 3mm in size). In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. In some embodiments, the capsule comprises HPMC (hydroxyl propyl methyl cellulose) or gelatin.

[0945] In some embodiments, the enteric coating comprises one enteric coating.

[0946] In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not identical (e.g., the inner and outer enteric coatings do not contain identical components in identical amounts).

[0947] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a polymethacrylate-based copolymer.

[0948] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

[0949] In some embodiments, the one enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[0950] In some embodiments, the one enteric coating comprises a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS
30 D).

[0951] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

[0952] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises an anionic polymeric material.

[0953] In some embodiments, the pharmaceutical agent comprises bacteria.

[0954] In some embodiments, the pharmaceutical agent comprises microbial extracellular vesicles (mEV).

[0955] In some embodiments, the pharmaceutical agent comprises bacteria and microbial extracellular vesicles (mEV).

[0956] In some embodiments, the pharmaceutical agent has one or more beneficial immune effects outside the gastrointestinal tract, e.g., when the solid dosage form is orally administered.

[0957] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract (e.g., outside of the small intestine) in the subject, e.g., when the solid dosage form is orally administered.

[0958] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[0959] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine (e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[0960] In some embodiments, the pharmaceutical agent comprises isolated bacteria (e.g., from one or more strains of bacteria (e.g., bacteria of interest) (e.g., a therapeutically effective amount thereof)). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is the isolated bacteria (e.g., bacteria of interest).

[0961] In some embodiments, the pharmaceutical agent comprises bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

[0962] In some embodiments, the pharmaceutical agent comprises live bacteria.

[0963] In some embodiments, the pharmaceutical agent comprises dead bacteria.

[0964] In some embodiments, the pharmaceutical agent comprises non-replicating bacteria.

[0965] In some embodiments, the pharmaceutical agent comprises bacteria from one strain of microbe (e.g., bacteria).

[0966] In some embodiments, the bacteria are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient) (e.g., a powder form).

[0967] In some embodiments, the bacteria are gamma irradiated.

[0968] In some embodiments, the bacteria are UV irradiated.

[0969] In some embodiments, the bacteria are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).

[0970] In some embodiments, the bacteria are acid treated.

[0971] In some embodiments, the bacteria are oxygen sparged (e.g., at 0.1 vvm for two hours).

[0972] In some embodiments, the bacteria are Gram positive bacteria.

[0973] In some embodiments, the bacteria are Gram negative bacteria.

[0974] In some embodiments, the bacteria are aerobic bacteria.

[0975] In some embodiments, the bacteria are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[0976] In some embodiments, the bacteria are acidophile bacteria.

[0977] In some embodiments, the bacteria are alkaliphile bacteria.

[0978] In some embodiments, the bacteria are neutralophile bacteria.

[0979] In some embodiments, the bacteria are fastidious bacteria.

[0980] In some embodiments, the bacteria are nonfastidious bacteria.

[0981] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[0982] In some embodiments, the bacteria are a bacterial strain listed in Table 1, Table 2, or Table 3.

[0983] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[0984] In some embodiments, the bacteria are a bacterial strain listed in Table J.

[0985] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[0986] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae .

[0987] In some embodiments, the bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0988] In some embodiments, the bacteria are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[0989] In some embodiments, the bacteria are of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one//a.

[0990] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.

[0991] In some embodiments, the bacteria are Prevotella histicola bacteria.

[0992] In some embodiments, the bacteria are Bifidobacterium animalis bacteria.

[0993] In some embodiments, the bacteria are Veil/one/la parvula bacteria.

[0994] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.
In some embodiments, the Lactococcus lactis cremoris bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[0995] In some embodiments, the bacteria are Prevotella bacteria. In some embodiments, the Prevotella bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are Prevotella Strain B 50329 (NRRL accession number B 50329).

[0996] In some embodiments, the bacteria are Bifidobacterium bacteria. In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are Bifidobacterium bacteria deposited as ATCC
designation number PTA-125097.

[0997] In some embodiments, the bacteria are Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 99%
genomic, 16S
and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are Veil/one/la bacteria deposited as ATCC designation number PTA-125691.

[0998] In some embodiments, the bacteria are from Ruminococcus gnavus bacteria.
In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[0999] In some embodiments, the bacteria are Megasphaera sp. bacteria. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are Megasphaera sp. bacteria deposited as ATCC
designation number PTA-126770.

[1000] In some embodiments, the bacteria are Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696.

[1001] In some embodiments, the bacteria are Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[1002] In some embodiments, the bacteria are of the family Acidaminococcaceae, Alcahgenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae .

[1003] In some embodiments, the bacteria are of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[1004] In some embodiments, the bacteria are Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium an/malls, or Bifidobacterium breve bacteria.

[1005] In some embodiments, the bacteria are BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[1006] In some embodiments, the bacteria are Blautia hydrogenotrophica bacteria.

[1007] In some embodiments, the bacteria are Blautia stercoris bacteria.

[1008] In some embodiments, the bacteria are Blautia w exlerae bacteria.

[1009] In some embodiments, the bacteria are Enterococcus gallinarum bacteria.

[1010] In some embodiments, the bacteria are Enterococcus faecium bacteria.

[1011] In some embodiments, the bacteria are Bifidobacterium bifidium bacteria.

[1012] In some embodiments, the bacteria are Bifidobacterium breve bacteria.

[1013] In some embodiments, the bacteria are Bifidobacterium longum bacteria.

[1014] In some embodiments, the bacteria are Roseburia hominis bacteria.

[1015] In some embodiments, the bacteria are Bacteroides thetaiotaomicron bacteria.

[1016] In some embodiments, the bacteria are Bacteroides coprocola bacteria.

[1017] In some embodiments, the bacteria are Erysipelatoclostridium ramosum bacteria.

[1018] In some embodiments, the bacteria are Megasphera massiliensis bacteria.

[1019] In some embodiments, the bacteria are Eubacterium bacteria.

[1020] In some embodiments, the bacteria are Parabacteroides distasonis bacteria.

[1021] In some embodiments, the bacteria are Lactobacillus plantarum bacteria.

[1022] In some embodiments, the bacteria are bacteria of the Negativicutes class.

[1023] In some embodiments, the bacteria are of the Veillonellaceae family.

[1024] In some embodiments, the bacteria are of the Selenomonadaceae family.

[1025] In some embodiments, the bacteria are of the Acidaminococcaceae family.

[1026] In some embodiments, the bacteria are of the Sporomusaceae family.

[1027] In some embodiments, the bacteria are of the Megasphaera genus.

[1028] In some embodiments, the bacteria are of the Selenomonas genus.

[1029] In some embodiments, the bacteria are of the Propionospora genus.

[1030] In some embodiments, the bacteria are of the Acidaminococcus genus.

[1031] In some embodiments, the bacteria are Megasphaera sp. bacteria.

[1032] In some embodiments, the bacteria are Selenomonas felix bacteria.

[1033] In some embodiments, the bacteria are Acidaminococcus intestini bacteria.

[1034] In some embodiments, the bacteria are Propionospora sp. bacteria.

[1035] In some embodiments, the bacteria are bacteria of the Clostridia class.

[1036] In some embodiments, the bacteria are of the Oscillospriraceae family.

[1037] In some embodiments, the bacteria are of the Faecalibacterium genus.

[1038] In some embodiments, the bacteria are of the Fournierella genus.

[1039] In some embodiments, the bacteria are of the Harryflintia genus.

[1040] In some embodiments, the bacteria are of the Agathobaculum genus.

[1041] In some embodiments, the bacteria are Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[1042] In some embodiments, the bacteria are Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[1043] In some embodiments, the bacteria are Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[1044] In some embodiments, the bacteria are Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[1045] In some embodiments, the bacteria are a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[1046] In some embodiments, the bacteria are of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the bacteria are of order Bacteroidales .
In some embodiments, the bacteria are of the family Porphyromonoadaceae . In some embodiments, the bacteria are of the family Prevotellaceae . In some embodiments, the bacteria are of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Bacteroidia that stain Gram negative. In some embodiments, the bacteria are of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[1047] In some embodiments, the bacteria are of the class Clostridia [phylum Firmicutes]. In some embodiments, the bacteria are of the order Eubacteriales.
In some embodiments, the bacteria are of the family Oscillispiraceae . In some embodiments, the bacteria are of the family Lachnospiraceae . In some embodiments, the bacteria are of the family Peptostreptococcaceae. In some embodiments, the bacteria are of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the bacteria are of the class Clostridia that stain Gram negative. In some embodiments, the bacteria are of the class Clostridia that stain Gram positive. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[1048] In some embodiments, the bacteria are of the class Negativicutes [phylum Firmicutes]. In some embodiments, the bacteria are of the order Veillonellales. In some embodiments, the bacteria are of the family Veillonelloceae. In some embodiments, the bacteria are of the order Selenomonadales. In some embodiments, the bacteria are of the family Selenomonadaceae. In some embodiments, the bacteria are of the family Sporomusaceae . In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Negativicutes that stain Gram negative. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[1049] In some embodiments, the bacteria are of the class Synergistia [phylum Synergistota]. In some embodiments, the bacteria are of the order Synergi stales. In some embodiments, the bacteria are of the family Synergistaceae . In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Synergistia that stain Gram negative. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[1050] In some embodiments, the bacteria are bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[1051] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[1052] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[1053] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[1054] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[1055] In some embodiments, the bacteria are bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[1056] In some embodiments, the pharmaceutical agent comprises isolated mEVs (e.g., from one or more strains of bacteria (e.g., bacteria of interest)) (e.g., a therapeutically effective amount thereof). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is isolated mEV of bacteria (e.g., bacteria of interest).

[1057] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise secreted mEVs (smEVs).

[1058] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise processed mEVs (pmEVs).

[1059] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from bacteria that have been gamma irradiated, UV
irradiated, heat inactivated, acid treated, or oxygen sparged.

[1060] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from live bacteria.

[1061] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from dead bacteria.

[1062] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from non-replicating bacteria.

[1063] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs are from one strain of bacteria.

[1064] In some embodiments, the mEVs are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient).

[1065] In some embodiments, the mEVs are gamma irradiated.

[1066] In some embodiments, the mEVs are UV irradiated.

[1067] In some embodiments, the mEVs are heat inactivated (e.g., at 50 C
for two hours or at 90 C for two hours).

[1068] In some embodiments, the mEVs are acid treated.

[1069] In some embodiments, the mEVs are oxygen sparged (e.g., at 0.1 vvm for two hours).

[1070] In some embodiments, the mEVs are from Gram positive bacteria.

[1071] In some embodiments, the mEVs are from Gram negative bacteria.

[1072] In some embodiments, the mEVs are from aerobic bacteria.

[1073] In some embodiments, the mEVs are from anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[1074] In some embodiments, the mEVs are from acidophile bacteria.

[1075] In some embodiments, the mEVs are from alkaliphile bacteria.

[1076] In some embodiments, the mEVs are from neutralophile bacteria.

[1077] In some embodiments, the mEVs are from fastidious bacteria.

[1078] In some embodiments, the mEVs are from nonfastidious bacteria.

[1079] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[1080] In some embodiments, the mEVs are from a bacterial strain listed in Table 1, Table 2, or Table 3.

[1081] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[1082] In some embodiments, the mEVs are from a bacterial strain listed in Table J.

[1083] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[1084] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae .

[1085] In some embodiments, the mEVs are from bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[1086] In some embodiments, the mEVs are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[1087] In some embodiments, the mEVs are from bacteria of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one//a.

[1088] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria.

[1089] In some embodiments, the mEVs are from Prevotella histicola bacteria.

[1090] In some embodiments, the mEVs are from Bifidobacterium animalis bacteria.

[1091] In some embodiments, the mEVs are from Veil/one/la parvula bacteria.

[1092] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria. In some embodiments, the Lactococcus lactis cremoris bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[1093] In some embodiments, the mEVs are from Prevotella bacteria. In some embodiments, the Prevotella bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are from a strain comprising at least 99% genomic, 16S
and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are from Prevotella Strain B 50329 (NRRL accession number B 50329).

[1094] In some embodiments, the mEVs are from Bifidobacterium bacteria.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are from Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.

[1095] In some embodiments, the mEVs are from Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from Veil/one/la bacteria deposited as ATCC
designation number PTA-125691.

[1096] In some embodiments, the mEVs are from Ruminococcus gnavus bacteria. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[1097] In some embodiments, the mEVs are from Megasphaera sp. bacteria.
In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770.
In some embodiments, the Megasphaera sp. bacteria are from Megasphaera sp.
bacteria deposited as ATCC designation number PTA-126770.

[1098] In some embodiments, the mEVs are from Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696.

[1099] In some embodiments, the mEVs are from Harryflintia acetispora bacteria.
In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[1100] In some embodiments, the mEVs are from bacteria of the family Acidaminococcaceae, Alcahgenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae.

[1101] In some embodiments, the mEVs are from bacteria of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[1102] In some embodiments, the mEVs are from Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium an/malls, or Bifidobacterium breve bacteria.

[1103] In some embodiments, the mEVs are from BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[1104] In some embodiments, the mEVs are from Blautia hydrogenotrophica bacteria.

[1105] In some embodiments, the mEVs are from Blautia stercoris bacteria.

[1106] In some embodiments, the mEVs are from Blautia w exlerae bacteria.

[1107] In some embodiments, the mEVs are from Enterococcus gallinarum bacteria.

[1108] In some embodiments, the mEVs are from Enterococcus faecium bacteria.

[1109] In some embodiments, the mEVs are from Bifidobacterium bifidium bacteria.

[1110] In some embodiments, the mEVs are from Bifidobacterium breve bacteria.

[1111] In some embodiments, the mEVs are from Bifidobacterium longum bacteria.

[1112] In some embodiments, the mEVs are from Roseburia hominis bacteria.

[1113] In some embodiments, the mEVs are from Bacteroides thetaiotaomicron bacteria.

[1114] In some embodiments, the mEVs are from Bacteroides coprocola bacteria.

[1115] In some embodiments, the mEVs are from Erysipelatoclostridium ramosum bacteria.

[1116] In some embodiments, the mEVs are from Megasphera massiliensis bacteria.

[1117] In some embodiments, the mEVs are from Eubacterium bacteria.

[1118] In some embodiments, the mEVs are from Parabacteroides distasonis bacteria.

[1119] In some embodiments, the mEVs are from Lactobacillus plantarum bacteria.

[1120] In some embodiments, the mEVs are from bacteria of the Negativicutes class.

[1121] In some embodiments, the mEVs are from bacteria of the Veillonellaceae family.

[1122] In some embodiments, the mEVs are from bacteria of the Selenomonadaceae family.

[1123] In some embodiments, the mEVs are from bacteria of the Acidaminococcaceae family.

[1124] In some embodiments, the mEVs are from bacteria of the Sporomusaceae family.

[1125] In some embodiments, the mEVs are from bacteria of the Megasphaera genus.

[1126] In some embodiments, the mEVs are from bacteria of the Selenomonas genus.

[1127] In some embodiments, the mEVs are from bacteria of the Propionospora genus.

[1128] In some embodiments, the mEVs are from bacteria of the Acidaminococcus genus.

[1129] In some embodiments, the mEVs are from Megasphaera sp. bacteria.

[1130] In some embodiments, the mEVs are from Selenomonas felix bacteria.

[1131] In some embodiments, the mEVs are from Acidaminococcus intestini bacteria.

[1132] In some embodiments, the mEVs are from Propionospora sp. bacteria.

[1133] In some embodiments, the mEVs are from bacteria of the Clostridia class.

[1134] In some embodiments, the mEVs are from bacteria of the Oscillospriraceae family.

[1135] In some embodiments, the mEVs are from bacteria of the Faecalibacterium genus.

[1136] In some embodiments, the mEVs are from bacteria of the Fournierella genus.

[1137] In some embodiments, the mEVs are from bacteria of the Harryflintia genus.

[1138] In some embodiments, the mEVs are from bacteria of the Agathobaculum genus.

[1139] In some embodiments, the mEVs are from Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[1140] In some embodiments, the mEVs are from Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[1141] In some embodiments, the mEVs are from Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[1142] In some embodiments, the mEVs are from Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[1143] In some embodiments, the mEVs are from a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[1144] In some embodiments, the mEVs are from bacteria of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the mEVs are from bacteria of order Bacteroidales. In some embodiments, the mEVs are from bacteria of the family Porphyromonoadaceae . In some embodiments, the mEVs are from bacteria of the family Prevotellaceae. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Bacteroidia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[1145] In some embodiments, the mEVs are from bacteria of the class Clostridia [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Eubacteriales. In some embodiments, the mEVs are from bacteria of the family Oscillispiraceae. In some embodiments, the mEVs are from bacteria of the family Lachnospiraceae . In some embodiments, the mEVs are from bacteria of the family Peptostreptococcaceae. In some embodiments, the mEVs are from bacteria of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram positive. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[1146] In some embodiments, the mEVs are from bacteria of the class Negativicutes [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Veil/one/la/es. In some embodiments, the mEVs are from bacteria of the family Veillonelloceae. In some embodiments, the mEVs are from bacteria of the order Selenomonadales. In some embodiments, the mEVs are from bacteria of the family Selenomonadaceae. In some embodiments, the mEVs are from bacteria of the family Sporomusaceae . In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm.
In some embodiments, the mEVs are from bacteria of the class Negativicutes that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[1147] In some embodiments, the mEVs are from bacteria of the class Synergistia [phylum Synergistota]. In some embodiments, the mEVs are from bacteria of the order Synergistales. In some embodiments, the mEVs are from bacteria of the family Synergistaceae. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Synergistia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[1148] In some embodiments, the mEVs are from bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[1149] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[1150] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[1151] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[1152] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[1153] In some embodiments, the mEVs are from bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[1154] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 10 to about 2 x 1012 (e.g., about 3 x 1010 or about 1.5 x 1011 or about 1.5 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 1010 to about 2 x 1012 (e.g., about 1.6 x 1011 or about 8 x 1011 or about 9.6 x 1011 about 12.8 x 1011 or about 1.6 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or per total number of minitablets in a capsule.

[1155] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 109, about 3 x 109, about 5 x 109, about 1.5 x 1010, about 3 x 1010, about 5 x 1010, about 1.5 x 1011, about 1.5 x 1012, or about 2 x 1012 cells, wherein the dose is per capsule or per total number of minitablets in a capsule.

[1156] In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 105 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 1010 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule or per total number of minitablets in a capsule.

[1157] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 10 mg to about 3500 mg, wherein the dose is per capsule or per total number of minitablets in a capsule.

[1158] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 30 mg to about1300 mg (by weight of bacteria and/or mEVs) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg, wherein the dose is per capsule or per total number of minitablets in a capsule.

[1159] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 2x106 to about 2x10'6 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule or per total number of minitablets in a capsule.

[1160] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 5 mg to about 900 mg total protein (e.g., wherein total protein is determined by Bradford assay or BCA), wherein the dose is per capsule or per total number of minitablets in a capsule.

[1161] In some embodiments, the solid dosage form further comprises one or more additional pharmaceutical agents.

[1162] In some embodiments, the solid dosage form further comprises an excipient (e.g., an excipient described herein, e.g., a diluent, a binder and/or an adhesive, a disintegrant, a lubricant and/or a glidant, a coloring agent, a flavoring agent, and/or a sweetening agent).

[1163] In some aspects, the disclosure provides a method for preparing a capsule comprising an enterically coated minitablet comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:

[1164] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;

[1165] b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a minitablet;

[1166] c) enterically coating the minitablet (e.g., thereby preparing the enterically coated minitablet), and

[1167] d) loading the capsule with the enterically coated minitablet (e.g., a size 0 capsule can contain about 31 to about 35 (e.g., 33) minitablets, wherein the minitablets are 3mm in size),

[1168] thereby preparing the capsule.

[1169] In some embodiments, the method further comprises banding the capsule after loading the capsule. In some embodiments, the capsule is banded with an HPMC-based banding solution.

[1170] In some embodiments, the minitablet (e.g., enterically coated minitablet) is a lmm minitablet, 1.5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet.
In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. In some embodiments, the capsule comprises HPMC (hydroxyl propyl methyl cellulose) or gelatin.

[1171] In some embodiments, the enteric coating comprises one enteric coating.

[1172] In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not identical (e.g., the inner and outer enteric coatings do not contain identical components in identical amounts).

[1173] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a polymethacrylate-based copolymer.

[1174] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

[1175] In some embodiments, the one enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[1176] In some embodiments, the one enteric coating comprises a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS
30 D).

[1177] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

[1178] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises an anionic polymeric material.

[1179] In some embodiments, the pharmaceutical agent comprises bacteria.

[1180] In some embodiments, the pharmaceutical agent comprises microbial extracellular vesicles (mEV).

[1181] In some embodiments, the pharmaceutical agent comprises bacteria and microbial extracellular vesicles (mEV).

[1182] In some embodiments, the pharmaceutical agent has one or more beneficial immune effects outside the gastrointestinal tract, e.g., when the solid dosage form is orally administered.

[1183] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract (e.g., outside of the small intestine) in the subject, e.g., when the solid dosage form is orally administered.

[1184] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[1185] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine (e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[1186] In some embodiments, the pharmaceutical agent comprises isolated bacteria (e.g., from one or more strains of bacteria (e.g., bacteria of interest) (e.g., a therapeutically effective amount thereof)). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is the isolated bacteria (e.g., bacteria of interest).

[1187] In some embodiments, the pharmaceutical agent comprises bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

[1188] In some embodiments, the pharmaceutical agent comprises live bacteria.

[1189] In some embodiments, the pharmaceutical agent comprises dead bacteria.

[1190] In some embodiments, the pharmaceutical agent comprises non-replicating bacteria.

[1191] In some embodiments, the pharmaceutical agent comprises bacteria from one strain of microbe (e.g., bacteria).

[1192] In some embodiments, the bacteria are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient) (e.g., a powder form).

[1193] In some embodiments, the bacteria are gamma irradiated.

[1194] In some embodiments, the bacteria are UV irradiated.

[1195] In some embodiments, the bacteria are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).

[1196] In some embodiments, the bacteria are acid treated.

[1197] In some embodiments, the bacteria are oxygen sparged (e.g., at 0.1 vvm for two hours).

[1198] In some embodiments, the bacteria are Gram positive bacteria.

[1199] In some embodiments, the bacteria are Gram negative bacteria.

[1200] In some embodiments, the bacteria are aerobic bacteria.

[1201] In some embodiments, the bacteria are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[1202] In some embodiments, the bacteria are acidophile bacteria.

[1203] In some embodiments, the bacteria are alkaliphile bacteria.

[1204] In some embodiments, the bacteria are neutralophile bacteria.

[1205] In some embodiments, the bacteria are fastidious bacteria.

[1206] In some embodiments, the bacteria are nonfastidious bacteria.

[1207] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[1208] In some embodiments, the bacteria are a bacterial strain listed in Table 1, Table 2, or Table 3.

[1209] In some embodiments, the bacteria are of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[1210] In some embodiments, the bacteria are a bacterial strain listed in Table J.

[1211] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[1212] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae .

[1213] In some embodiments, the bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[1214] In some embodiments, the bacteria are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[1215] In some embodiments, the bacteria are of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one//a.

[1216] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.

[1217] In some embodiments, the bacteria are Prevotella histicola bacteria.

[1218] In some embodiments, the bacteria are Bifidobacterium animalis bacteria.

[1219] In some embodiments, the bacteria are Veil/one/la parvula bacteria.

[1220] In some embodiments, the bacteria are Lactococcus lactis cremoris bacteria.
In some embodiments, the Lactococcus lactis cremoris bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[1221] In some embodiments, the bacteria are Prevotella bacteria. In some embodiments, the Prevotella bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL

accession number B 50329). In some embodiments, the Prevotella bacteria are Prevotella Strain B 50329 (NRRL accession number B 50329).

[1222] In some embodiments, the bacteria are Bifidobacterium bacteria. In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are Bifidobacterium bacteria deposited as ATCC
designation number PTA-125097.

[1223] In some embodiments, the bacteria are Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are a strain comprising at least 99%
genomic, 16S
and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one//a bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are Veil/one/la bacteria deposited as ATCC designation number PTA-125691.

[1224] In some embodiments, the bacteria are from Ruminococcus gnavus bacteria.
In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[1225] In some embodiments, the bacteria are Megasphaera sp. bacteria. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are Megasphaera sp. bacteria deposited as ATCC
designation number PTA-126770.

[1226] In some embodiments, the bacteria are Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696.

[1227] In some embodiments, the bacteria are Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[1228] In some embodiments, the bacteria are of the family Acidaminococcaceae, Alcahgenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae.

[1229] In some embodiments, the bacteria are of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[1230] In some embodiments, the bacteria are Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium an/malls, or Bifidobacterium breve bacteria.

[1231] In some embodiments, the bacteria are BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[1232] In some embodiments, the bacteria are Blautia hydrogenotrophica bacteria.

[1233] In some embodiments, the bacteria are Blautia stercoris bacteria.

[1234] In some embodiments, the bacteria are Blautia w exlerae bacteria.

[1235] In some embodiments, the bacteria are Enterococcus gallinarum bacteria.

[1236] In some embodiments, the bacteria are Enterococcus faecium bacteria.

[1237] In some embodiments, the bacteria are Bifidobacterium bifidium bacteria.

[1238] In some embodiments, the bacteria are Bifidobacterium breve bacteria.

[1239] In some embodiments, the bacteria are Bifidobacterium longum bacteria.

[1240] In some embodiments, the bacteria are Roseburia hominis bacteria.

[1241] In some embodiments, the bacteria are Bacteroides thetaiotaomicron bacteria.

[1242] In some embodiments, the bacteria are Bacteroides coprocola bacteria.

[1243] In some embodiments, the bacteria are Erysipelatoclostridium ramosum bacteria.

[1244] In some embodiments, the bacteria are Megasphera massiliensis bacteria.

[1245] In some embodiments, the bacteria are Eubacterium bacteria.

[1246] In some embodiments, the bacteria are Parabacteroides distasonis bacteria.

[1247] In some embodiments, the bacteria are Lactobacillus plantarum bacteria.

[1248] In some embodiments, the bacteria are bacteria of the Negativicutes class.

[1249] In some embodiments, the bacteria are of the Veillonellaceae family.

[1250] In some embodiments, the bacteria are of the Selenomonadaceae family.

[1251] In some embodiments, the bacteria are of the Acidaminococcaceae family.

[1252] In some embodiments, the bacteria are of the Sporomusaceae family.

[1253] In some embodiments, the bacteria are of the Megasphaera genus.

[1254] In some embodiments, the bacteria are of the Selenomonas genus.

[1255] In some embodiments, the bacteria are of the Propionospora genus.

[1256] In some embodiments, the bacteria are of the Acidaminococcus genus.

[1257] In some embodiments, the bacteria are Megasphaera sp. bacteria.

[1258] In some embodiments, the bacteria are Selenomonas felix bacteria.

[1259] In some embodiments, the bacteria are Acidaminococcus intestini bacteria.

[1260] In some embodiments, the bacteria are Propionospora sp. bacteria.

[1261] In some embodiments, the bacteria are bacteria of the Clostridia class.

[1262] In some embodiments, the bacteria are of the Oscillospriraceae family.

[1263] In some embodiments, the bacteria are of the Faecalibacterium genus.

[1264] In some embodiments, the bacteria are of the Fournierella genus.

[1265] In some embodiments, the bacteria are of the Harryflintia genus.

[1266] In some embodiments, the bacteria are of the Agathobaculum genus.

[1267] In some embodiments, the bacteria are Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[1268] In some embodiments, the bacteria are Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[1269] In some embodiments, the bacteria are Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[1270] In some embodiments, the bacteria are Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[1271] In some embodiments, the bacteria are a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[1272] In some embodiments, the bacteria are of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the bacteria are of order Bacteroidales.
In some embodiments, the bacteria are of the family Porphyromonoadaceae. In some embodiments, the bacteria are of the family Prevotellaceae. In some embodiments, the bacteria are of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Bacteroidia that stain Gram negative. In some embodiments, the bacteria are of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[1273] In some embodiments, the bacteria are of the class Clostridia [phylum Firmicutes]. In some embodiments, the bacteria are of the order Eubacteriales.
In some embodiments, the bacteria are of the family Oscillispiraceae. In some embodiments, the bacteria are of the family Lachnospiraceae. In some embodiments, the bacteria are of the family Peptostreptococcaceae. In some embodiments, the bacteria are of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the bacteria are of the class Clostridia that stain Gram negative. In some embodiments, the bacteria are of the class Clostridia that stain Gram positive. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the bacteria are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[1274] In some embodiments, the bacteria are of the class Negativicutes [phylum Firmicutes]. In some embodiments, the bacteria are of the order Veillonellales. In some embodiments, the bacteria are of the family Veillonelloceae. In some embodiments, the bacteria are of the order Selenomonadales. In some embodiments, the bacteria are of the family Selenomonadaceae. In some embodiments, the bacteria are of the family Sporomusaceae. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Negativicutes that stain Gram negative. In some embodiments, the bacteria are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[1275] In some embodiments, the bacteria are of the class Synergistia [phylum Synergistota]. In some embodiments, the bacteria are of the order Synergi stales. In some embodiments, the bacteria are of the family Synergistaceae . In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria are of the class Synergistia that stain Gram negative. In some embodiments, the bacteria are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[1276] In some embodiments, the bacteria are bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[1277] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[1278] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[1279] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[1280] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[1281] In some embodiments, the bacteria are bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecal/bacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[1282]

[1283] In some embodiments, the pharmaceutical agent comprises isolated mEVs (e.g., from one or more strains of bacteria (e.g., bacteria of interest)) (e.g., a therapeutically effective amount thereof). E.g., wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is isolated mEV of bacteria (e.g., bacteria of interest).

[1284] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise secreted mEVs (smEVs).

[1285] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs comprise processed mEVs (pmEVs).

[1286] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from bacteria that have been gamma irradiated, UV
irradiated, heat inactivated, acid treated, or oxygen sparged.

[1287] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from live bacteria.

[1288] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from dead bacteria.

[1289] In some embodiments, the pharmaceutical agent comprises pmEVs and the pmEVs are produced from non-replicating bacteria.

[1290] In some embodiments, the pharmaceutical agent comprises mEVs and the mEVs are from one strain of bacteria.

[1291] In some embodiments, the mEVs are lyophilized (e.g., the lyophilized product further comprises a pharmaceutically acceptable excipient).

[1292] In some embodiments, the mEVs are gamma irradiated.

[1293] In some embodiments, the mEVs are UV irradiated.

[1294] In some embodiments, the mEVs are heat inactivated (e.g., at 50 C
for two hours or at 90 C for two hours).

[1295] In some embodiments, the mEVs are acid treated.

[1296] In some embodiments, the mEVs are oxygen sparged (e.g., at 0.1 vvm for two hours).

[1297] In some embodiments, the mEVs are from Gram positive bacteria.

[1298] In some embodiments, the mEVs are from Gram negative bacteria.

[1299] In some embodiments, the mEVs are from aerobic bacteria.

[1300] In some embodiments, the mEVs are from anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

[1301] In some embodiments, the mEVs are from acidophile bacteria.

[1302] In some embodiments, the mEVs are from alkaliphile bacteria.

[1303] In some embodiments, the mEVs are from neutralophile bacteria.

[1304] In some embodiments, the mEVs are from fastidious bacteria.

[1305] In some embodiments, the mEVs are from nonfastidious bacteria.

[1306] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table 1, Table 2, or Table 3.

[1307] In some embodiments, the mEVs are from a bacterial strain listed in Table 1, Table 2, or Table 3.

[1308] In some embodiments, the mEVs are from bacteria of a taxonomic group (e.g., class, order, family, genus, species or strain) listed in Table J.

[1309] In some embodiments, the mEVs are from a bacterial strain listed in Table J.

[1310] In some embodiments, the Gram negative bacteria belong to class Negativicutes.

[1311] In some embodiments, the Gram negative bacteria belong to family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae .

[1312] In some embodiments, the mEVs are from bacteria of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[1313] In some embodiments, the mEVs are Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacteria.

[1314] In some embodiments, the mEVs are from bacteria of the genus Lactococcus, Prevotella, Bifidobacterium, or Veil/one/la.

[1315] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria.

[1316] In some embodiments, the mEVs are from Prevotella histicola bacteria.

[1317] In some embodiments, the mEVs are from Bifidobacterium animalis bacteria.

[1318] In some embodiments, the mEVs are from Veil/one/la parvula bacteria.

[1319] In some embodiments, the mEVs are from Lactococcus lactis cremoris bacteria. In some embodiments, the Lactococcus lactis cremoris bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacteria are from Lactococcus lactis cremoris Strain A (ATCC designation number PTA-125368).

[1320] In some embodiments, the mEVs are from Prevotella bacteria. In some embodiments, the Prevotella bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are from a strain comprising at least 99% genomic, 16S
and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the Prevotella bacteria are from Prevotella Strain B 50329 (NRRL accession number B 50329).

[1321] In some embodiments, the mEVs are from Bifidobacterium bacteria.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.
In some embodiments, the Bifidobacterium bacteria are from a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacteria are from Bifidobacterium bacteria deposited as ATCC designation number PTA-125097.

[1322] In some embodiments, the mEVs are from Veil/one/la bacteria. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veil/one/la bacteria deposited as ATCC designation number PTA-125691. In some embodiments, the Veil/one/la bacteria are from Veil/one//a bacteria deposited as ATCC
designation number PTA-125691.

[1323] In some embodiments, the mEVs are from Ruminococcus gnavus bacteria. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are from Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.

[1324] In some embodiments, the mEVs are from Megasphaera sp. bacteria.
In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 90%
(or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770.
In some embodiments, the Megasphaera sp. bacteria are from Megasphaera sp.
bacteria deposited as ATCC designation number PTA-126770.

[1325] In some embodiments, the mEVs are from Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are from Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696.

[1326] In some embodiments, the mEVs are from Harryflintia acetispora bacteria.
In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are from Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.

[1327] In some embodiments, the mEVs are from bacteria of the family Acidaminococcaceae, Alcaligenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeraceae, Mycobacteriaceae, Neisseriaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae, or Veillonellaceae.

[1328] In some embodiments, the mEVs are from bacteria of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[1329] In some embodiments, the mEVs are from Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium an/malls, or Bifidobacterium breve bacteria.

[1330] In some embodiments, the mEVs are from BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholder/a, Klebsiella quasipneumoniae ssp similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis, or Neisseria bacteria.

[1331] In some embodiments, the mEVs are from Blautia hydrogenotrophica bacteria.

[1332] In some embodiments, the mEVs are from Blautia stercoris bacteria.

[1333] In some embodiments, the mEVs are from Blautia wexlerae bacteria.

[1334] In some embodiments, the mEVs are from Enterococcus gallinarum bacteria.

[1335] In some embodiments, the mEVs are from Enterococcus faecium bacteria.

[1336] In some embodiments, the mEVs are from Bifidobacterium bifidium bacteria.

[1337] In some embodiments, the mEVs are from Bifidobacterium breve bacteria.

[1338] In some embodiments, the mEVs are from Bifidobacterium longum bacteria.

[1339] In some embodiments, the mEVs are from Roseburia hominis bacteria.

[1340] In some embodiments, the mEVs are from Bacteroides thetaiotaomicron bacteria.

[1341] In some embodiments, the mEVs are from Bacteroides coprocola bacteria.

[1342] In some embodiments, the mEVs are from Erysipelatoclostridium ramosum bacteria.

[1343] In some embodiments, the mEVs are from Megasphera massiliensis bacteria.

[1344] In some embodiments, the mEVs are from Eubacterium bacteria.

[1345] In some embodiments, the mEVs are from Parabacteroides distasonis bacteria.

[1346] In some embodiments, the mEVs are from Lactobacillus plantarum bacteria.

[1347] In some embodiments, the mEVs are from bacteria of the Negativicutes class.

[1348] In some embodiments, the mEVs are from bacteria of the Veillonellaceae family.

[1349] In some embodiments, the mEVs are from bacteria of the Selenomonadaceae family.

[1350] In some embodiments, the mEVs are from bacteria of the Acidaminococcaceae family.

[1351] In some embodiments, the mEVs are from bacteria of the Sporomusaceae family.

[1352] In some embodiments, the mEVs are from bacteria of the Megasphaera genus.

[1353] In some embodiments, the mEVs are from bacteria of the Selenomonas genus.

[1354] In some embodiments, the mEVs are from bacteria of the Propionospora genus.

[1355] In some embodiments, the mEVs are from bacteria of the Acidaminococcus genus.

[1356] In some embodiments, the mEVs are from Megasphaera sp. bacteria.

[1357] In some embodiments, the mEVs are from Selenomonas felix bacteria.

[1358] In some embodiments, the mEVs are from Acidaminococcus intestini bacteria.

[1359] In some embodiments, the mEVs are from Propionospora sp. bacteria.

[1360] In some embodiments, the mEVs are from bacteria of the Clostridia class.

[1361] In some embodiments, the mEVs are from bacteria of the Oscillospriraceae family.

[1362] In some embodiments, the mEVs are from bacteria of the Faecalibacterium genus.

[1363] In some embodiments, the mEVs are from bacteria of the Fournierella genus.

[1364] In some embodiments, the mEVs are from bacteria of the Harryflintia genus.

[1365] In some embodiments, the mEVs are from bacteria of the Agathobaculum genus.

[1366] In some embodiments, the mEVs are from Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.

[1367] In some embodiments, the mEVs are from Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[1368] In some embodiments, the mEVs are from Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.

[1369] In some embodiments, the mEVs are from Agathobaculum sp. (e.g., Agathobaculum sp. Strain A) bacteria.

[1370] In some embodiments, the mEVs are from a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).

[1371] In some embodiments, the mEVs are from bacteria of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the mEVs are from bacteria of order Bacteroidales . In some embodiments, the mEVs are from bacteria of the family Porphyromonoadaceae . In some embodiments, the mEVs are from bacteria of the family Prevotellaceae . In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Bacteroidia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[1372] In some embodiments, the mEVs are from bacteria of the class Clostridia [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Eubacteriales. In some embodiments, the mEVs are from bacteria of the family Oscillispiraceae. In some embodiments, the mEVs are from bacteria of the family Lachnospiraceae. In some embodiments, the mEVs are from bacteria of the family Peptostreptococcaceae. In some embodiments, the mEVs are from bacteria of the family Clostridiales family XIII/ Incertae sec/is 41. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia that stain Gram positive. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.

[1373] In some embodiments, the mEVs are from bacteria of the class Negativicutes [phylum Firmicutes]. In some embodiments, the mEVs are from bacteria of the order Veil/one/la/es. In some embodiments, the mEVs are from bacteria of the family Veillonelloceae. In some embodiments, the mEVs are from bacteria of the order Selenomonadales. In some embodiments, the mEVs are from bacteria of the family Selenomonadaceae. In some embodiments, the mEVs are from bacteria of the family Sporomusaceae. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm.
In some embodiments, the mEVs are from bacteria of the class Negativicutes that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[1374] In some embodiments, the mEVs are from bacteria of the class Synergistia [phylum Synergistota]. In some embodiments, the mEVs are from bacteria of the order Synergi stales. In some embodiments, the mEVs are from bacteria of the family Synergistaceae. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the mEVs are from bacteria of the class Synergistia that stain Gram negative. In some embodiments, the mEVs are from bacteria of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.

[1375] In some embodiments, the mEVs are from bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.

[1376] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.

[1377] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.

[1378] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veillonella.

[1379] In some embodiments, the bacteria produce tryptophan metabolites.
In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

[1380] In some embodiments, the mEVs are from bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus mass/liens/s, Faecal/bacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.

[1381] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 107 to about 2 x 1012 (e.g., about 3 x 1010 or about 1.5 x 1011 or about 1.5 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 1010 to about 2 x 1012 (e.g., about 1.6 x 1011 or about 8 x 1011 or about 9.6 x 1011 about 12.8 x 1011 or about 1.6 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or per total number of minitablets in a capsule.

[1382] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 109, about 3 x 109, about 5 x 109, about 1.5 x 1010, about 3 x 1010, about 5 x 1010, about 1.5 x 1011, about 1.5 x 1012, or about 2 x 1012 cells, wherein the dose is per capsule or per total number of minitablets in a capsule.

[1383] In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 105 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 1010 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or per total number of minitablets in a capsule.

[1384] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 10 mg to about 3500 mg, wherein the dose is per capsule or per total number of minitablets in a capsule.

[1385] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of drug substance that contains the pharmaceutical agent (e.g., bacteria and/or mEVs) is about 30 mg to about1300 mg (by weight of bacteria and/or mEVs) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg, wherein the dose is per capsule or per total number of minitablets in a capsule.

[1386] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 2x106 to about 2x10'6 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule or per total number of minitablets in a capsule.

[1387] In some embodiments, the pharmaceutical agent comprises bacteria and/or mEVs and the dose of pharmaceutical agent (e.g., bacteria and/or mEVs) is about 5 mg to about 900 mg total protein (e.g., wherein total protein is determined by Bradford assay or BCA), wherein the dose is per capsule or per total number of minitablets in a capsule.

[1388] In some embodiments, the capsule or minitablet further comprises one or more additional pharmaceutical agents.

[1389] In some embodiments, the capsule or minitablet further comprises an excipient (e.g., an excipient described herein, e.g., a diluent, a binder and/or an adhesive, a disintegrant, a lubricant and/or a glidant, a coloring agent, a flavoring agent, and/or a sweetening agent).
Brief Description of the Drawings

[1390] Figure 1 is a graph showing the effects of L. Lactis spp. cremoris solid dosage forms on ear thickness 24 hours after challenge in a DTH model.
Detailed Description Definitions

[1391] "Adjuvant" or "Adjuvant therapy" broadly refers to an agent that affects an immunological or physiological response in a subject (e.g., human). For example, an adjuvant might increase the presence of an antigen over time or to an area of interest like a tumor, help absorb an antigen presenting cell antigen, activate macrophages and lymphocytes and support the production of cytokines. By changing an immune response, an adjuvant might permit a smaller dose of an immune interacting agent to increase the effectiveness or safety of a particular dose of the immune interacting agent.
For example, an adjuvant might prevent T cell exhaustion and thus increase the effectiveness or safety of a particular immune interacting agent.

[1392] "Administration" broadly refers to a route of administration of a composition (e.g., a pharmaceutical composition such as a solid dosage form that contains a pharmaceutical agent as described herein) to a subject. Examples of routes of administration include oral administration, rectal administration, topical administration, inhalation (nasal) or injection. Administration by injection includes intravenous (IV), intramuscular (IM), intratumoral (IT) and subcutaneous (SC) administration. A
pharmaceutical composition described herein can be administered in any form by any effective route, including but not limited to intratumoral, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), intradermal, ophthalmic, (intra)nasally, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, vaginal, intra-arterial, and intrathecal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), implanted, intravesical, intrapulmonary, intraduodenal, intragastrical, and intrabronchial. In preferred embodiments, a pharmaceutical composition described herein is administered orally, rectally, intratumorally, topically, intravesically, by injection into or adjacent to a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously. In another preferred embodiment, a pharmaceutical composition described herein is administered orally, intratumorally, or intravenously. In another embodiment, a pharmaceutical composition described herein is administered orally.

[1393] As used herein, the term "antibody" may refer to both an intact antibody and an antigen binding fragment thereof. Intact antibodies are glycoproteins that include at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain includes a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain includes a light chain variable region (abbreviated herein as VI) and a light chain constant region. The \Tx and \/1_, regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
Each \Tx and \/1_, is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The term "antibody" includes, for example, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multi specific antibodies (e.g., bispecific antibodies), single-chain antibodies and antigen-binding antibody fragments.

[1394] The terms "antigen binding fragment" and "antigen-binding portion"
of an antibody, as used herein, refer to one or more fragments of an antibody that retain the ability to bind to an antigen. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include Fab, Fab', F(ab')2, Fv, scFv, disulfide linked Fv, Fd, diabodies, single-chain antibodies, NANOBODIES , isolated CDRH3, and other antibody fragments that retain at least a portion of the variable region of an intact antibody. These antibody fragments can be obtained using conventional recombinant and/or enzymatic techniques and can be screened for antigen binding in the same manner as intact antibodies.

[1395] "Cancer" broadly refers to an uncontrolled, abnormal growth of a host's own cells leading to invasion of surrounding tissue and potentially tissue distal to the initial site of abnormal cell growth in the host. Major classes include carcinomas which are cancers of the epithelial tissue (e.g., skin, squamous cells); sarcomas which are cancers of the connective tissue (e.g., bone, cartilage, fat, muscle, blood vessels, etc.);
leukemias which are cancers of blood forming tissue (e.g., bone marrow tissue); lymphomas and myelomas which are cancers of immune cells; and central nervous system cancers which include cancers from brain and spinal tissue. "Cancer(s) and" "neoplasm(s)" are used herein interchangeably. As used herein, "cancer" refers to all types of cancer or neoplasm or malignant tumors including leukemias, carcinomas and sarcomas, whether new or recurring. Specific examples of cancers are: carcinomas, sarcomas, myelomas, leukemias, lymphomas and mixed type tumors. Non-limiting examples of cancers are new or recurring cancers of the brain, melanoma, bladder, breast, cervix, colon, head and neck, kidney, lung, non-small cell lung, mesothelioma, ovary, prostate, sarcoma, stomach, uterus and medulloblastoma. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a metastasis.

[1396] A "carbohydrate" refers to a sugar or polymer of sugars. The terms "saccharide," "polysaccharide," "carbohydrate," and "oligosaccharide" may be used interchangeably. Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually one on each carbon atom of the molecule. Carbohydrates generally have the molecular formula CnH2nOn. A carbohydrate may be a monosaccharide, a disaccharide, trisaccharide, oligosaccharide, or polysaccharide. The most basic carbohydrate is a monosaccharide, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose, and fructose. Disaccharides are two joined monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose. Typically, an oligosaccharide includes between three and six monosaccharide units (e.g., raffinose, stachyose), and polysaccharides include six or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified saccharide units such as 2'-deoxyribose wherein a hydroxyl group is removed, 2'-fluororibose wherein a hydroxyl group is replaced with a fluorine, or N-acetylglucosamine, a nitrogen-containing form of glucose (e.g., 2'-fluororibose, deoxyribose, and hexose).
Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.

[1397] "Cellular augmentation" broadly refers to the influx of cells or expansion of cells in an environment that are not substantially present in the environment prior to administration of a composition and not present in the composition itself Cells that augment the environment include immune cells, stromal cells, bacterial and fungal cells.
Environments of particular interest are the microenvironments where cancer cells reside or locate. In some instances, the microenvironment is a tumor microenvironment or a tumor draining lymph node. In other instances, the microenvironment is a pre-cancerous tissue site or the site of local administration of a composition or a site where the composition will accumulate after remote administration.

[1398] "Clade" refers to the OTUs or members of a phylogenetic tree that are downstream of a statistically valid node in a phylogenetic tree. The clade comprises a set of terminal leaves in the phylogenetic tree that is a distinct monophyletic evolutionary unit and that share some extent of sequence similarity.

[1399] A "combination" of bacteria from two or more strains includes the physical co-existence of the bacteria, either in the same material or product or in physically connected products, as well as the temporal co-administration or co-localization of the bacteria from the two or more strains.

[1400] A "combination" of mEVs (such as smEVs and/or pmEVs) from two or more microbial (such as bacteria) strains includes the physical co-existence of the microbes from which the mEVs (such as smEVs and/or pmEVs) are obtained, either in the same material or product or in physically connected products, as well as the temporal co-administration or co-localization of the mEVs (such as smEVs and/or pmEVs) from the two or more strains.

[1401] The term "decrease" or "deplete" means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 1/100, 1/1000, 1/10,000, 1/100,000, 1/1,000,000 or undetectable after treatment when compared to a pre-treatment state. Properties that may be decreased include the number of immune cells, bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites; the level of a cytokine; or another physical parameter (such as ear thickness (e.g., in a DTH animal model) or tumor size).

[1402] "Dysbiosis" refers to a state of the microbiota or niicrobiome of the gut or other body area, including, e.g., mucosal or skin surfaces (or any other microbiome niche) in which the normal diversity and/or function of the host gut ruicrobiome ecological networks ( "microbiorne") are disrupted. A state of dysbiosis may result in a diseased state, or it may be unhealthy under only certain conditions or only if present for a prolonged period. Dysbiosis may be due to a variety of factors, including, environmental factors, infectious agents host genotype, host diet and/or stress. A. dysbiosi.s may result in: a change (e.g., increase or decrease) in the prevalence of one or more bacteria types (e.g., anaerobic), species and/or strains, change (e.g., increase or decrease) in diversity of the host microbiorne population composition; a change (e.g., increase or reduction) of one or more populations of symbiont organisms resulting in a reduction or loss of one or more beneficial effects; overgrowth of one or more populations of pathogens (e.g., pathogenic bacteria);
and/or the presence of, and/or overgrowth of, symbiotic organisms that cause disease only when certain conditions are present.

[1403] The term "ecological consortium" is a group of bacteria which trades metabolites and positively co-regulates one another, in contrast to two bacteria which induce host synergy through activating complementary host pathways for improved efficacy.
11404] The term "effective dose" or "effective amount" is an amount of a pharmaceutical agent that is effective to achieve a desired therapeutic response in a subject for a particular agent, composition, and mode of administration.
[1405] As used herein, "engineered bacteria" are any bacteria that have been genetically altered from their natural state by human activities, and the progeny of any such bacteria. Engineered bacteria include, for example, the products of targeted genetic modification, the products of random mutagenesis screens and the products of directed evolution.
[1406] The term "epitope" means a protein determinant capable of specific binding to an antibody or T cell receptor. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains. Certain epitopes can be defined by a particular sequence of amino acids to which an antibody is capable of binding.
[1407] The term "gene" is used broadly to refer to any nucleic acid associated with a biological function. The term "gene" applies to a specific genomic sequence, as well as to a cDNA or an mRNA encoded by that genomic sequence.
[1408] "Identity" as between nucleic acid sequences of two nucleic acid molecules can be determined as a percentage of identity using known computer algorithms such as the "FASTA" program, using for example, the default parameters as in Pearson et at. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et at., Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F., et al., J Molec Biol 215:403 (1990); Guide to Huge Computers, Mrtin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo et at.
(1988) SIAM J
Applied Math 48:1073). For example, the BLAST function of the National Center for Biotechnology Information database can be used to determine identity. Other commercially or publicly available programs include, DNAStar "MegAlign" program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG) "Gap" program (Madison Wis.)).
[1409] As used herein, the term "immune disorder" refers to any disease, disorder or disease symptom caused by an activity of the immune system, including autoimmune diseases, inflammatory diseases and allergies. Immune disorders include, but are not limited to, autoimmune diseases (e.g., psoriasis, atopic dermatitis, lupus, scleroderma, hemolytic anemia, vasculitis, type one diabetes, Grave's disease, rheumatoid arthritis, multiple sclerosis, Goodpasture's syndrome, pernicious anemia and/or myopathy), inflammatory diseases (e.g., acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis and/or interstitial cystitis), and/or an allergies (e.g., food allergies, drug allergies and/or environmental allergies).
[1410] "Immunotherapy" is treatment that uses a subject's immune system to treat disease (e.g., immune disease, inflammatory disease, metabolic disease, cancer) and includes, for example, checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cells, and dendritic cell therapy.
[1411] The term "increase" means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 4-fold, 10-fold, 100-fold, 101\3 fold, 101\4 fold, 101\5 fold, 101\6 fold, and/or 101\7 fold greater after treatment when compared to a pre-treatment state. Properties that may be increased include the number of immune cells, bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites; the level of a cytokine; or another physical parameter (such as ear thickness (e.g., in a DTH animal model) or tumor size).
[1412] "Innate immune agonists" or "immuno-adjuvants" are small molecules, proteins, or other agents that specifically target innate immune receptors including Toll-Like Receptors (TLR), NOD receptors, RLRs, C-type lectin receptors, STING-cGAS

Pathway components, inflammasome complexes. For example, LPS is a TLR-4 agonist that is bacterially derived or synthesized and aluminum can be used as an immune stimulating adjuvant. immuno-adjuvants are a specific class of broader adjuvant or adjuvant therapy.

Examples of STING agonists include, but are not limited to, 2'3'- cGAMP, 3'3'-cGAMP, c-di-AMP, c-di-GMP, 2'2'-cGAMP, and 2'3'-cGAM(PS)2 (Rp/Sp) (Rp, Sp-isomers of the bis-phosphorothioate analog of 2'3'-cGAMP). Examples of TLR agonists include, but are not limited to, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10 and TLRI 1. Examples of NOD agonists include, but are not limited to, N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyldipeptide (MDP)), gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), and desmuramylpeptides (D1V113).
[1413] The "internal transcribed spacer" or "ITS" is a piece of non-functional RNA
located between structural ribosomal RNAs (rRNA) on a common precursor transcript often used for identification of eukaryotic species in particular fungi. The rRNA of fungi that forms the core of the ribosome is transcribed as a signal gene and consists of the 8S, 5.8S and 28S regions with ITS4 and 5 between the 8S and 5.8S and 5.8S and 28S
regions, respectively. These two intercistronic segments between the 18S and 5.8S and 5.8S and 28S
regions are removed by splicing and contain significant variation between species for barcoding purposes as previously described (Schoch et al Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi.
PNAS
109:6241-6246. 2012). 18S rDNA is traditionally used for phylogenetic reconstruction however the ITS can serve this function as it is generally highly conserved but contains hypervariable regions that harbor sufficient nucleotide diversity to differentiate genera and species of most fungus.
[1414] The term "isolated" or "enriched" encompasses a microbe (such as a bacterium), an mEV (such as an smEV and/or pmEV) or other entity or substance that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting), and/or (2) produced, prepared, purified, and/or manufactured by the hand of man. Isolated microbes or mEVs may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated microbes or mEVs are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99%
pure. As used herein, a substance is "pure" if it is substantially free of other components.
The terms "purify," "purifying" and "purified" refer to a microbe or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production. A microbe or a microbial population or mEVs may be considered purified if it is isolated at or after production, such as from a material or environment containing the microbe or microbial population, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90%
and still be considered "isolated." In some embodiments, purified microbes or microbial population or mEVs are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. In the instance of microbial compositions provided herein, the one or more microbial types present in the composition can be independently purified from one or more other microbes produced and/or present in the material or environment containing the microbial type. Microbial compositions and the microbial components thereof are generally purified from residual habitat products.
[1415] As used herein a "lipid" includes fats, oils, triglycerides, cholesterol, phospholipids, fatty acids in any form including free fatty acids. Fats, oils and fatty acids can be saturated, unsaturated (cis or trans) or partially unsaturated (cis or trans).
[1416] "Metabolite" as used herein refers to any and all molecular compounds, compositions, molecules, ions, co-factors, catalysts or nutrients used as substrates in any cellular or microbial metabolic reaction or resulting as product compounds, compositions, molecules, ions, co-factors, catalysts or nutrients from any cellular or microbial metabolic reaction.
[1417] "Microbe" refers to any natural or engineered organism characterized as an archaeaon, parasite, bacterium, fungus, microscopic alga, protozoan, and the stages of development or life cycle stages (e.g., vegetative, spore (including sporulation, dormancy, and germination), latent, biofilm) associated with the organism. Examples of gut microbes include: Actinomyces graevenitzii, Actinomyces odontolyticus, Akkermansia mucimphila, Bacteroides caccae, Bacteroides fragilis, Bacteroides putredinis, Bacteroides thetaiotaomicron, Bacteroides vultagus, Bifidobacterium adolescentis, Bifidobacterium bifidum, Bilophila wadsworthia, Blautia, Butyrivibrio, Campylobacter gracilis, Clostridia cluster III, Clostridia cluster IV, Clostridia cluster IX (Acidaminococcaceae group), Clostridia cluster XI, Clostridia cluster XIII (Peptostreptococcus group), Clostridia cluster XIV, Clostridia cluster XV, Collinsella aerofaciens, Coprococcus, Corynebacterium sunsvallense, Desulfomonas pigra, Dorea formicigenerans, Dorea longicatena, Escherichia coil, Eubacterium hadrum, Eubacterium rectale, Faecallbacteria prausnitzii, Gemella, Lactococcus, Lanchnospira, Mollicutes cluster XVI, Mollicutes cluster XVIII, Prevotella, Rothia mucilaginosa, Ruminococcus callidus, Ruminococcus gnavus, Ruminococcus torques, and Streptococcus.
[1418] "Microbial extracellular vesicles" (mEVs) can be obtained from microbes such as bacteria, archaea, fungi, microscopic algae, protozoans, and parasites. In some embodiments, the mEVs are obtained from bacteria. mEVs include secreted microbial extracellular vesicles (smEVs) and processed microbial extracellular vesicles (pmEVs).
"Secreted microbial extracellular vesicles" (smEVs) are naturally-produced vesicles derived from microbes. smEVs are comprised of microbial lipids and/or microbial proteins and/or microbial nucleic acids and/or microbial carbohydrate moieties, and are isolated from culture supernatant. The natural production of these vesicles can be artificially enhanced (e.g., increased) or decreased through manipulation of the environment in which the bacterial cells are being cultured (e.g., by media or temperature alterations). Further, smEV
compositions may be modified to reduce, increase, add, or remove microbial components or foreign substances to alter efficacy, immune stimulation, stability, immune stimulatory capacity, stability, organ targeting (e.g., lymph node), absorption (e.g., gastrointestinal), and/or yield (e.g., thereby altering the efficacy). As used herein, the term "purified smEV
composition" or "smEV composition" refers to a preparation of smEVs that have been separated from at least one associated substance found in a source material (e.g., separated from at least one other microbial component) or any material associated with the smEVs in any process used to produce the preparation. It can also refer to a composition that has been significantly enriched for specific components. "Processed microbial extracellular vesicles"
(pmEVs) are a non-naturally-occurring collection of microbial membrane components that have been purified from artificially lysed microbes (e.g., bacteria) (e.g., microbial membrane components that have been separated from other, intracellular microbial cell components), and which may comprise particles of a varied or a selected size range, depending on the method of purification. A pool of pmEVs is obtained by chemically disrupting (e.g., by lysozyme and/or lysostaphin) and/or physically disrupting (e.g., by mechanical force) microbial cells and separating the microbial membrane components from the intracellular components through centrifugation and/or ultracentrifugation, or other methods. The resulting pmEV mixture contains an enrichment of the microbial membranes and the components thereof (e.g., peripherally associated or integral membrane proteins, lipids, glycans, polysaccharides, carbohydrates, other polymers), such that there is an increased concentration of microbial membrane components, and a decreased concentration (e.g., dilution) of intracellular contents, relative to whole microbes. For gram-positive bacteria, pmEVs may include cell or cytoplasmic membranes. For gram-negative bacteria, a pmEV may include inner and outer membranes. pmEVs may be modified to increase purity, to adjust the size of particles in the composition, and/or modified to reduce, increase, add or remove, microbial components or foreign substances to alter efficacy, immune stimulation, stability, immune stimulatory capacity, stability, organ targeting (e.g., lymph node), absorption (e.g., gastrointestinal), and/or yield (e.g., thereby altering the efficacy).
pmEVs can be modified by adding, removing, enriching for, or diluting specific components, including intracellular components from the same or other microbes. As used herein, the term "purified pmEV composition" or "pmEV composition" refers to a preparation of pmEVs that have been separated from at least one associated substance found in a source material (e.g., separated from at least one other microbial component) or any material associated with the pmEVs in any process used to produce the preparation. It can also refer to a composition that has been significantly enriched for specific components.
[1419] "Microbiome" broadly refers to the microbes residing on or in body site of a subject or patient. Microbes in a microbiome may include bacteria, viruses, eukaryotic microorganisms, and/or viruses. Individual microbes in a microbiome may be metabolically active, dormant, latent, or exist as spores, may exist planktonically or in biofilms, or may be present in the microbiome in sustainable or transient manner. The microbiome may be a commensal or healthy-state microbiome or a disease-state or dysbiotic microbiome. The microbiome may be native to the subject or patient, or components of the microbiome may be modulated, introduced, or depleted due to changes in health state (e.g., precancerous or cancerous state) or treatment conditions (e.g., antibiotic treatment, exposure to different microbes). In some aspects, the microbiome occurs at a mucosal surface. In some aspects, the microbiome is a gut microbiome. In some aspects, the microbiome is a tumor microbiome.
[1420] A "microbiome profile" or a "microbiome signature" of a tissue or sample refers to an at least partial characterization of the bacterial makeup of a microbiome. In some embodiments, a microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more bacterial strains are present or absent in a microbiome. In some embodiments, a microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more cancer-associated bacterial strains are present in a sample. In some embodiments, the microbiome profile indicates the relative or absolute amount of each bacterial strain detected in the sample. In some embodiments, the microbiome profile is a cancer-associated microbiome profile. A cancer-associated microbiome profile is a microbiome profile that occurs with greater frequency in a subject who has cancer than in the general population. In some embodiments, the cancer-associated microbiome profile comprises a greater number of or amount of cancer-associated bacteria than is normally present in a microbiome of an otherwise equivalent tissue or sample taken from an individual who does not have cancer.
[1421] "Modified" in reference to a bacteria broadly refers to a bacteria that has undergone a change from its wild-type form. Bacterial modification can result from engineering bacteria. Examples of bacterial modifications include genetic modification, gene expression modification, phenotype modification, formulation modification, chemical modification, and dose or concentration. Examples of improved properties are described throughout this specification and include, e.g., attenuation, auxotrophy, homing, or antigenicity. Phenotype modification might include, by way of example, bacteria growth in media that modify the phenotype of a bacterium such that it increases or decreases virulence.
[1422] An "oncobiome" as used herein comprises tumorigenic and/or cancer-associated microbiota, wherein the microbiota comprises one or more of a virus, a bacterium, a fungus, a protist, a parasite, or another microbe.
[1423] "Oncotrophic" or "oncophilic" microbes and bacteria are microbes that are highly associated or present in a cancer microenvironment. They may be preferentially selected for within the environment, preferentially grow in a cancer microenvironment or hone to a said environment.
[1424] "Operational taxonomic units" and "OTU(s)" refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g., the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species. In some embodiments the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence. In other embodiments, the entire genomes of two entities are sequenced and compared. In another embodiment, select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared. For 16S, OTUs that share > 97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU.
See e.g., Claesson MJ, Wang Q, O'Sullivan 0, Greene-Diniz R, Cole JR, Ross RP, and O'Toole PW. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions.
Nucleic Acids Res 38: e200. Konstantinidis KT, Ramette A, and Tiedje JM. 2006.
The bacterial species definition in the genomic era. Philos Trans R Soc Lond B
Biol Sci 361:
1929-1940. For complete genomes, MLSTs, specific genes, other than 16S, or sets of genes OTUs that share > 95% average nucleotide identity are considered the same OTU.
See e.g., Achtman M, and Wagner M. 2008. Microbial diversity and the genetic nature of microbial species. Nat. Rev. Microbiol. 6: 431-440. Konstantinidis KT, Ramette A, and Tiedje JIM.
2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361: 1929-1940. OTUs are frequently defined by comparing sequences between organisms. Generally, sequences with less than 95% sequence identity are not considered to form part of the same OTU. OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g., "house-keeping"
genes), or a combination thereof. Operational Taxonomic Units (OTUs) with taxonomic assignments made to, e.g., genus, species, and phylogenetic clade are provided herein.
[1425] As used herein, a gene is "overexpressed" in a bacteria if it is expressed at a higher level in an engineered bacteria under at least some conditions than it is expressed by a wild-type bacteria of the same species under the same conditions. Similarly, a gene is "underexpressed" in a bacteria if it is expressed at a lower level in an engineered bacteria under at least some conditions than it is expressed by a wild-type bacteria of the same species under the same conditions.
[1426] The terms "polynucleotide", and "nucleic acid" are used interchangeably.
They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof Polynucleotides may have any three-dimensional structure, and may perform any function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), micro RNA

(miRNA), silencing RNA (siRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
A
polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. A polynucleotide may be further modified, such as by conjugation with a labeling component. In all nucleic acid sequences provided herein, U
nucleotides are interchangeable with T nucleotides.
[1427] As used herein, the term "preventing" a disease or condition in a subject refers to administering to the subject to a pharmaceutical treatment, e.g., the administration of one or more agents (e.g., pharmaceutical agent), such that onset of at least one symptom of the disease or condition is delayed or prevented.
[1428] As used herein, a substance is "pure" if it is substantially free of other components. The terms "purify," "purifying" and "purified" refer to an mEV
(such as an smEV and/or a pmEV) preparation or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production. An mEV (such as an smEV and/or a pmEV) preparation or compositions may be considered purified if it is isolated at or after production, such as from one or more other bacterial components, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered "purified." In some embodiments, purified mEVs (such as smEVs and/or pmEVs) are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99%
pure.
mEV (such as an smEV and/or a pmEV) compositions (or preparations) are, e.g., purified from residual habitat products.
[1429] As used herein, the term "purified mEV composition" or "mEV
composition" refers to a preparation that includes mEVs (such as smEVs and/or pmEVs) that have been separated from at least one associated substance found in a source material (e.g., separated from at least one other bacterial component) or any material associated with the mEVs (such as smEVs and/or pmEVs) in any process used to produce the preparation.
It also refers to a composition that has been significantly enriched or concentrated. In some embodiments, the mEVs (such as smEVs and/or pmEVs) are concentrated by 2 fold, 3-fold, 4-fold, 5-fold, 10-fold, 100-fold, 1000-fold, 10,000-fold or more than 10,000 fold.

[1430] "Residual habitat products" refers to material derived from the habitat for microbiota within or on a subject. For example, fermentation cultures of microbes can contain contaminants, e.g., other microbe strains or forms (e.g., bacteria, virus, mycoplasm, and/or fungus). For example, microbes live in feces in the gastrointestinal tract, on the skin itself, in saliva, mucus of the respiratory tract, or secretions of the genitourinary tract (i.e., biological matter associated with the microbial community). Substantially free of residual habitat products means that the microbial composition no longer contains the biological matter associated with the microbial environment on or in the culture or human or animal subject and is 100% free, 99% free, 98% free, 97% free, 96% free, or 95% free of any contaminating biological matter associated with the microbial community.
Residual habitat products can include abiotic materials (including undigested food) or it can include unwanted microorganisms. Substantially free of residual habitat products may also mean that the microbial composition contains no detectable cells from a culture contaminant or a human or animal and that only microbial cells are detectable. In one embodiment, substantially free of residual habitat products may also mean that the microbial composition contains no detectable viral (including bacteria, viruses (e.g., phage)), fungal, mycoplasmal contaminants. In another embodiment, it means that fewer than 1x10-2%, 1x10-3%, 1x10-4%, 1x10-5%, 1x10-6%, 1x10-7%, 1x10-8% of the viable cells in the microbial composition are human or animal, as compared to microbial cells. There are multiple ways to accomplish this degree of purity, none of which are limiting. Thus, contamination may be reduced by isolating desired constituents through multiple steps of streaking to single colonies on solid media until replicate (such as, but not limited to, two) streaks from serial single colonies have shown only a single colony morphology. Alternatively, reduction of contamination can be accomplished by multiple rounds of serial dilutions to single desired cells (e.g., a dilution of 10-8 or 10-9), such as through multiple 10-fold serial dilutions. This can further be confirmed by showing that multiple isolated colonies have similar cell shapes and Gram staining behavior. Other methods for confirming adequate purity include genetic analysis (e.g., PCR, DNA sequencing), serology and antigen analysis, enzymatic and metabolic analysis, and methods using instrumentation such as flow cytometry with reagents that distinguish desired constituents from contaminants.
[1431] As used herein, "specific binding" refers to the ability of an antibody to bind to a predetermined antigen or the ability of a polypeptide to bind to its predetermined binding partner. Typically, an antibody or polypeptide specifically binds to its predetermined antigen or binding partner with an affinity corresponding to a KD of about 10' M or less, and binds to the predetermined antigen/binding partner with an affinity (as expressed by Ku) that is at least 10 fold less, at least 100 fold less or at least 1000 fold less than its affinity for binding to a non-specific and unrelated antigen/binding partner (e.g., BSA, casein). Alternatively, specific binding applies more broadly to a two-component system where one component is a protein, lipid, or carbohydrate or combination thereof and engages with the second component which is a protein, lipid, carbohydrate or combination thereof in a specific way.
[1432] "Strain" refers to a member of a bacterial species with a genetic signature such that it may be differentiated from closely-related members of the same bacterial species. The genetic signature may be the absence of all or part of at least one gene, the absence of all or part of at least on regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the absence ("curing") of at least one native plasmid, the presence of at least one recombinant gene, the presence of at least one mutated gene, the presence of at least one foreign gene (a gene derived from another species), the presence at least one mutated regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the presence of at least one non-native plasmid, the presence of at least one antibiotic resistance cassette, or a combination thereof Genetic signatures between different strains may be identified by PCR amplification optionally followed by DNA
sequencing of the genomic region(s) of interest or of the whole genome. In the case in which one strain (compared with another of the same species) has gained or lost antibiotic resistance or gained or lost a biosynthetic capability (such as an auxotrophic strain), strains may be differentiated by selection or counter-selection using an antibiotic or nutrient/metabolite, respectively.
[1433] The terms "subject" or "patient" refers to any mammal. A subject or a patient described as "in need thereof' refers to one in need of a treatment (or prevention) for a disease. Mammals (i.e., mammalian animals) include humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs), and household pets (e.g., dogs, cats, rodents). The subject may be a human. The subject may be a non-human mammal including but not limited to of a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.
The subject may be healthy, or may be suffering from a cancer at any developmental stage, wherein any of the stages are either caused by or opportunistically supported of a cancer associated or causative pathogen, or may be at risk of developing a cancer, or transmitting to others a cancer associated or cancer causative pathogen. In some embodiments, a subject has lung cancer, bladder cancer, prostate cancer, plasmacytoma, colorectal cancer, rectal cancer, Merkel Cell carcinoma, salivary gland carcinoma, ovarian cancer, and/or melanoma. The subject may have a tumor. The subject may have a tumor that shows enhanced macropinocytosis with the underlying genomics of this process including Ras activation. In other embodiments, the subject has another cancer. In some embodiments, the subject has undergone a cancer therapy.
[1434] As used herein, a "systemic effect" in a subject treated with a pharmaceutical composition containing bacteria or mEVs (e.g., a pharmaceutical agent comprising bacteria or mEVs) of the instant invention means a physiological effect occurring at one or more sites outside the gastrointestinal tract. Systemic effect(s) can result from immune modulation (e.g., via an increase and/or a reduction of one or more immune cell types or subtypes (e.g., CD8+ T cells) and/or one or more cytokines).
Such systemic effect(s) may be the result of the modulation by bacteria or mEVs of the instant invention on immune or other cells (such as epithelial cells) in the gastrointestinal tract which then, directly or indirectly, result in the alteration of activity (activation and/or deactivation) of one or more biochemical pathways outside the gastrointestinal tract. The systemic effect may include treating or preventing a disease or condition in a subject.
[1435] As used herein, the term "treating" a disease in a subject or "treating" a subject having or suspected of having a disease refers to administering to the subject to a pharmaceutical treatment, e.g., the administration of one or more agents (e.g., pharmaceutical agent), such that at least one symptom of the disease is decreased or prevented from worsening. Thus, in one embodiment, "treating" refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.
[1436] As used herein, a "type" of bacteria may be distinguished from other bacteria by: genus, species, sub-species, strain or by any other taxonomic categorization, whether based on morphology, physiology, genotype, protein expression or other characteristics known in the art.

Bacteria [1437] In certain aspects, the pharmaceutical agent of the solid dosage forms described herein comprises bacteria and/or microbial extracellular vesicles (mEVs) (such as smEVs and/or pmEVs). Within a pharmaceutical agent that contains bacteria and mEVs, the mEVs can be from the same bacterial origin (e.g., same strain) as the bacteria of the pharmaceutical agent. The pharmaceutical agent can contain bacteria and/or mEVs from one or more strains.
[1438] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are modified to reduce toxicity or other adverse effects, to enhance delivery) (e.g., oral delivery) (e.g., by improving acid resistance, muco-adherence and/or penetration and/or resistance to bile acids, digestive enzymes, resistance to anti-microbial peptides and/or antibody neutralization), to target desired cell types (e.g., M-cells, goblet cells, enterocytes, dendritic cells, macrophages), to enhance their immunomodulatory and/or therapeutic effect of the bacteria and/or mEVs (e.g., either alone or in combination with another pharmaceutical agent), and/or to enhance immune activation or suppression by the bacteria and/or mEVs (such as smEVs and/or pmEVs) (e.g., through modified production of polysaccharides, pili, fimbriae, adhesins). In some embodiments, the engineered bacteria described herein are modified to improve bacteria and/or mEV (such as smEV and/or pmEV) manufacturing (e.g., higher oxygen tolerance, stability, improved freeze-thaw tolerance, shorter generation times). For example, in some embodiments, the engineered bacteria described include bacteria harboring one or more genetic changes, such change being an insertion, deletion, translocation, or substitution, or any combination thereof, of one or more nucleotides contained on the bacterial chromosome or endogenous plasmid and/or one or more foreign plasmids, wherein the genetic change may result in the overexpression and/or underexpression of one or more genes. The engineered bacteria may be produced using any technique known in the art, including but not limited to site-directed mutagenesis, transposon mutagenesis, knock-outs, knock-ins, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light mutagenesis, transformation (chemically or by electroporation), phage transduction, directed evolution, or any combination thereof.
[1439] Examples of taxonomic groups (e.g., class, order, family, genus, species or strain) of bacteria that can be used as a source of bacteria and/or mEVs (such as smEVs and/or pmEVs) for a pharmaceutical agent described herein are provided herein (e.g., listed in Table 1, Table 2, and/or Table 3 and/or elsewhere in the specification (e.g., Table J)). In some embodiments, the bacterial strain is a bacterial strain having a genome that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity to a strain listed herein. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are oncotrophic bacteria. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are immunomodulatory bacteria. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are immunostimulatory bacteria. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are immunosuppressive bacteria. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are immunomodulatory bacteria. In certain embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are generated from a combination of bacterial strains provided herein. In some embodiments, the combination is a combination of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45 or 50 bacterial strains. In some embodiments, the combination includes the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are from bacterial strains listed herein and/or bacterial strains having a genome that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity to a strain listed herein (e.g., listed in Table 1, Table 2, and/or Table 3 and/or elsewhere in the specification (e.g., Table J)). In certain embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are generated from a bacterial strain provided herein. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are from a bacterial strain listed herein (e.g., listed in Table 1, Table 2, and/or Table 3 and/or elsewhere in the specification (e.g., Table Mand/or a bacterial strain having a genome that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity to a strain listed herein (e.g., listed in Table 1, Table 2, and/or Table 3 and/or elsewhere in the specification (e.g., Table J)).

[1440] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Gram negative bacteria.
[1441] In some embodiments, the Gram negative bacteria belong to the class Negativicutes. The Negativicutes represent a unique class of microorganisms as they are the only diderm members of the Firmicutes phylum. These anaerobic organisms can be found in the environment and are normal commensals of the oral cavity and GI tract of humans.
Because these organisms have an outer membrane, the yields of EVs from this class were investigated. It was found that on a per cell basis these bacteria produce a high number of vesicles (10-150 EVs/cell). The EVs from these organisms are broadly stimulatory and highly potent in in vitro assays. Investigations into their therapeutic applications in several oncology and inflammation in vivo models have shown their therapeutic potential. The Negativicutes class includes the families Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, and Sporomusaceae . The Negativicutes class includes the genera Megasphaera, Selenomonas, Propionospora, and Acidaminococcus. Exemplary Negativicutes species include, but are not limited to, Megasphaera sp., Selenomonas felix, Acidaminococcus intestine, and Propionospora sp.
[1442] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Gram positive bacteria.
[1443] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are aerobic bacteria.
[1444] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.
[1445] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are acidophile bacteria.
[1446] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are alkaliphile bacteria.
[1447] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are neutralophile bacteria.
[1448] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are fastidious bacteria.

[1449] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are nonfastidious bacteria.
[1450] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained or the mEVs themselves are lyophilized.
[1451] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained or the mEVs themselves are gamma irradiated (e.g., at 17.5 or 25 kGy).
[1452] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained or the mEVs themselves are UV
irradiated.
[1453] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained or the mEVs themselves are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).
[1454] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained or the mEVs themselves are acid treated.
[1455] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained or the mEVs themselves are oxygen sparged (e.g., at 0.1 vvm for two hours).
[1456] The phase of growth can affect the amount or properties of bacteria and/or mEVs produced by bacteria. For example, in the methods of mEVs preparation provided herein, mEVs can be isolated, e.g., from a culture, at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.
[1457] In certain embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained from obligate anaerobic bacteria.
Examples of obligate anaerobic bacteria include gram-negative rods (including the genera of Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Bilophila and Sutterella spp.), gram-positive cocci (primarily Peptostreptococcus spp.), gram-positive spore-forming (Clostridium spp.), non-spore-forming bacilli (Actinomyces, Prop/on/bacterium, Eubacterium, Lactobacillus and Bifidobacterium spp.), and gram-negative cocci (mainly Veil/one/la spp.). In some embodiments, the obligate anaerobic bacteria are of a genus selected from the group consisting of Agathobaculum, Atopobium, Blautia, Burkholderia, Die/ma, Longicatena, Paraclostridium, Turicibacter, and Tyzzerella.
[1458] The Negativicutes class includes the families Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, and Sporomusaceae. The Negativicutes class includes the genera Megasphaera, Selenomonas, Propionospora, and Acidaminococcus.
Exemplary Negativicutes species include, but are not limited to, Megasphaera sp., Selenomonas felix, Acidaminococcus intestini, and Propionospora sp.
[1459] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Negativicutes class.
[1460] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Veillonellaceae family.
[1461] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Selenomonadaceae family.
[1462] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Acidaminococcaceae family.
[1463] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Sporomusaceae family.
[1464] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Megasphaera genus.
[1465] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Selenomonas genus.
[1466] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Propionospora genus.
[1467] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Acidaminococcus genus.
[1468] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Megasphaera sp.
bacteria.
[1469] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Selenomonas felix bacteria.

[1470] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Acidaminococcus intestini bacteria.
[1471] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Propionospora sp.
bacteria.
[1472] The Oscillospriraceae family within the Clostridia class of microorganisms are common commensal organisms of vertebrates.
[1473] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Clostridia class.
[1474] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Oscillospriraceae family.
[1475] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Faecalibacterium genus.
[1476] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Fournierella genus.
[1477] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Harryflintia genus.
[1478] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Agathobaculum genus.
[1479] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.
[1480] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.
[1481] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.
[1482] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Agathobaculum sp.
(e.g., Agathobaculum sp. Strain A) bacteria.

[1483] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria of a genus selected from the group consisting of Escherichia, Klebsiella, Lactobacillus, Shigella, and Staphylococcus.
[1484] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are a species selected from the group consisting of Blautia massiliensis, Paraclostridium benzoelyticum, Dielma fastidiosa, Longicatena caecimuris, Lactococcus lactis cremoris, Tyzzerella nexilis, Hungatella effluvia, Klebsiella quasipneumoniae subsp. Simihpneumoniae, Klebsiella oxytoca, and Veillonella tobetsuensis.
[1485] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are a Prevotella bacteria selected from the group consisting of Prevotella albensis, Prevotella amnii, Prevotella bergensis, Prevotella bivia, Prevotella brevis, Prevotella bryantii, Prevotella buccae, Prevotella buccalis, Prevotella copri, Prevotella dentalis, Prevotella dent/cola, Prevotella disiens, Prevotella histicola, Prevotella intermedia, Prevotella maculosa, Prevotella marshii, Prevotella melaninogenica, Prevotella micans, Prevotella multiform/s, Prevotella nigrescens, Prevotella ()rails, Prevotella or/s, Prevotella oulorum, Prevotella pallens, Prevotella salivae, Prevotella stercorea, Prevotella tannerae, Prevotella timonensis, Prevotella jejuni, Prevotella aurantiaca, Prevotella baroniae, Prevotella colorans, Prevotella corporis, Prevotella dentasini, Prevotella enoeca, Prevotella falsenii, Prevotella fusca, Prevotella heparinolytica, Prevotella loescheii, Prevotella multisaccharivorax, Prevotella nanceiensis, Prevotella oryzae, Prevotella paludivivens, Prevotella pleuritidis, Prevotella ruminicola, Prevotella saccharolytica, Prevotella scopos, Prevotella shahii, Prevotella zoogleoformans, and Prevotella veroralis.
[1486] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are a strain of bacteria comprising a genomic sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%
sequence identity (e.g., at least 99.5% sequence identity, at least 99.6%
sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the genomic sequence of the strain of bacteria deposited with the ATCC Deposit number as provided in Table 3. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are a strain of bacteria comprising a 16S sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%
sequence identity (e.g., at least 99.5% sequence identity, at least 99.6%
sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the 16S sequence of the strain of bacteria deposited with the ATCC Deposit number as provided in Table 3.
[1487] The Negativicutes class includes the families Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, and Sporomusaceae. The Negativicutes class includes the genera Megasphaera, Selenomonas, Propionospora, and Acidaminococcus.
Exemplary Negativicutes species include, but are not limited to, Megasphaera sp., Selenomonas felix, Acidaminococcus intestini, and Propionospora sp.
[1488] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Negativicutes class.
[1489] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Veillonellaceae family.
[1490] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Selenomonadaceae family.
[1491] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Acidaminococcaceae family.
[1492] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Sporomusaceae family.
[1493] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Megasphaera genus.
[1494] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Selenomonas genus.
[1495] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Propionospora genus.
[1496] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Acidaminococcus genus.

[1497] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Megasphaera sp.
bacteria.
[1498] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Selenomonas felix bacteria.
[1499] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Acidaminococcus intestini bacteria.
[1500] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Propionospora sp.
bacteria.
[1501] The Oscillospriraceae family within the Clostridia class of microorganisms are common commensal organisms of vertebrates.
[1502] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Clostridia class.
[1503] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Oscillospriraceae family.
[1504] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Faecalibacterium genus.
[1505] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Fournierella genus.
[1506] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Harryflintia genus.
[1507] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the Agathobaculum genus.
[1508] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii Strain A) bacteria.
[1509] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Fournierella massiliensis (e.g., Fournierella massiliensis Strain A) bacteria.

[1510] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Harryflintia acetispora (e.g., Harryflintia ace tispora Strain A) bacteria.
[1511] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Agathobaculum sp.
(e.g., Agathobaculum sp. Strain A) bacteria.
[1512] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are a strain of Agathobaculum sp.
In some embodiments, the Agathobaculum sp. strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5%
sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Agathobaculum sp.
Strain A (ATCC Deposit Number PTA-125892). In some embodiments, the Agathobaculum sp. strain is the Agathobaculum sp. Strain A (ATCC Deposit Number PTA-125892).
[1513] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Bacteroidia [phylum Bacteroidota]. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria of order Bacteroidales. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Porphyromonoadaceae. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Prevotellaceae. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria of the class Bacteroidia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria of the class Bacteroidia that stain Gram negative. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria of the class Bacteroidia wherein the bacteria is diderm and the bacteria stain Gram negative.

[1514] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria of the class Clostridia [phylum Firmicutes]. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the order Eubacteriales. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Oscillispiraceae. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Lachnospiraceae. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Peptostreptococcaceae. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Clostridiales family XIII/ Incertae sedis 41. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Clostridia that stain Gram negative.
In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Clostridia that stain Gram positive. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram negative. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Clostridia wherein the cell envelope structure of the bacteria is monoderm and the bacteria stain Gram positive.
[1515] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Negativicutes [phylum Firmicutes]. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the order Veillonellales. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Veillonelloceae.
In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the order Selenomonadales. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria of the family Selenomonadaceae . In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Sporomusaceae. In some embodiments, t the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are the EVs are from bacteria of the class Negativicutes wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.
[1516] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Synergistia [phylum Synergistota]. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the order Synergistales. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the family Synergistaceae.
In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Synergistia that stain Gram negative. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are of the class Synergistia wherein the cell envelope structure of the bacteria is diderm and the bacteria stain Gram negative.
[1517] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are from one strain of bacteria, e.g., a strain provided herein.
[1518] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are from one strain of bacteria (e.g., a strain provided herein) or from more than one strain provided herein.
[1519] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Lactococcus lactis cremoris bacteria, e.g., a strain comprising at least 90% or at least 99% genomic, 16S
and/or CRISPR
sequence identity to the nucleotide sequence of the Lactococcus lactis cremoris Strain A
(ATCC designation number PTA-125368). In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Lactococcus bacteria, e.g., Lactococcus lactis cremoris Strain A (ATCC
designation number PTA-125368).
[1520] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Prevotella bacteria, e.g., a strain comprising at least 90% or at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL
accession number B 50329). In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Prevotella bacteria, e.g., Prevotella Strain B 50329 (NRRL accession number B 50329).
[1521] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Bifidobacterium bacteria, e.g., a strain comprising at least 90% or at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Bifidobacterium bacteria deposited as ATCC designation number PTA-125097. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Bifidobacterium bacteria, e.g., Bifidobacterium bacteria deposited as ATCC
designation number PTA-125097.
[1522] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Veillonella bacteria, e.g., a strain comprising at least 90% or at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Veillonella bacteria deposited as ATCC
designation number PTA-125691. In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Veillonella bacteria, e.g., Veillonella bacteria deposited as ATCC designation number PTA-125691.
[1523] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Ruminococcus gnavus bacteria. In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC
designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695. In some embodiments, the Ruminococcus gnavus bacteria are Ruminococcus gnavus bacteria deposited as ATCC designation number PTA-126695.
[1524] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Megasphaera sp.
bacteria. In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770.
In some embodiments, the Megasphaera sp. bacteria are a strain comprising at least 99%
genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp.bacteria deposited as ATCC designation number PTA-126770. In some embodiments, the Megasphaera sp. bacteria are Megasphaera sp. bacteria deposited as ATCC designation number PTA-126770.
[1525] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR
sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited as ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited as ATCC
designation number PTA-126696.
[1526] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are a strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited as ATCC
designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited as ATCC designation number PTA-126694.
[1527] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria that produce metabolites, e.g., the bacteria produce butyrate, iosine, proprionate, or tryptophan metabolites.
[1528] In some embodiments, the bacteria produce butyrate. In some embodiments, the bacteria are from the genus Blautia; Christensella; Copracoccus;
Eubacterium;
Lachnosperacea; Megasphaera; or Roseburia.
[1529] In some embodiments, the bacteria produce iosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Olsenella.
[1530] In some embodiments, the bacteria produce proprionate. In some embodiments, the bacteria are from the genus Akkermansia; Bacteriodes;
Dialister;
Eubacterium; Megasphaera; Parabacteriodes; Prevotella; Ruminococcus; or Veil/one/la.
[1531] In some embodiments, the bacteria produce tryptophan metabolites. In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.
[1532] In some embodiments, the bacteria of the pharmaceutical agent or from which the mEVs of the pharmaceutical agent are obtained are bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis or Roseburia intestinal/s.
Table 1: Bacteria by Class Class Order Family Genus Species Actinobacter Actinomycetales Mycobacteriaceae Mycobacterium Streptomycetaceae Sfreptomyces Sfreptomyces lividans, Streptomyces coelicolor, Streptomyces sudanesis, Streptomyces somaliensis Bifidobacteriales Bifidobacteriaceae Bifidobacterium Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium pseudocatenulatum Coriobacteriales Coriobacteriaceae Collinsella Collinsella aerofaciens Olsenella Olsenellafaecalis Propionibacteriales Propionibacteraceae Propionibacterium Bacilli Bacillales Bacillales incertae Gemella Gemella sedis family XI haemolysans, Gemella morbillorum Listeraceae Listeria Listeria monocytogenes, Listeria welshimeri Lactobacillales Enterococcaceae Enterococcus Enterococcus durans, Enterococcus faecium, Enterococcus faecalis, Enterococcus gallinarum, Enterococcus villorum Lactobacillus Lactobacillus casei, Lactobacillus fermentum, Lactococcus lactis cremoris, Lactobacillus mucosae, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, L.
salvarius Streptococcaceae Lactococcus Staphylococcus Staphylococcus aureus Sfreptococcus Sfreptococcus agalactiae, Streptococcus aureus, Streptococcus ausfrali, Streptococcus mutans, Streptococcus parasanguinis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus salivraius Bacteriodes Bacteroidales Bacteriodaceae Bacteriodes Bacteroides caccae, Bacteroides cellulosilyticus, Bacteroides coprocola, Bacteroides dorei, Bacteroides fragilis, Bacteroides ovatus, Bacteroides putredinis, Bacteroides salanifronis, Bacteroides thetaiotaomicron, Bacteroides vulgatus Odoribacteraceae Odoribacter Odoribacter splanchnicus Porphyromonadaceae Parabacteriodes Parabacteriodes distasonis, Parabacteroides goldsteinii, P
Parabacteriodes merdae Porphyromonas Porphyromonas gingivalis Prevotella Prevotella Prevotellaceae albensis, Prevotella amnii, Prevotella aurantiaca, Prevotella baroniae, Prevotella bergensis, Prevotella bivia, Prevotella brevis, Prevotella bryantii, Prevotella buccae, Prevotella buccalis, Prevotella colorans, Prevotella corporis, Prevotella copri, Prevotella dentalis, Prevotella dentasini, Prevotella denticola, Prevotella disiensõ
Prevotella enoeca, Prevotella falsenii, Prevotella fusca, Prevotella heparinolytica, Prevotella histicola, Prevotella intermedia, Prevotella jejuniõ
Prevotella loescheii, Prevotella maculosa, Prevotella marshii, Prevotella melaninogenica, Prevotella micans, Prevotella multiformis, Prevotella multisaccharivorax , Prevotella nanceiensis, Prevotella nigrescens, Prevotella oralis, Prevotella orisõ
Prevotella oryzae, Prevotella oulorum, Prevotella pal/ens, Prevotella paludivivens, Prevotella pleuritidis Prevotella rum inicola, Prevotella saccharolytica ,Prevotella salivae, Prevotella scopos, Prevotella shahii, Prevotella stercorea, Prevotella tannerae, Prevotella timonensis, Prevotella veroralis, Prevotella zoogleoformans Rikenellaceae Alstipes Alistipes communis , Alistipes dispar, A.
finegoldii, Alistipes indistinctus, Alistipes ihumii, Alistipes mops,, Alistipes massiliensisõ
Alistipes megaguti, Alistipes obesi , Alistipes onderdonkii, Alistipes provencensis, Alistipes putredinis, Alistipes senegalensisõ
Alistipes shahii, Alistipes timonensis Betaproteoba Burkholderiales Akaligenaceae Paenalcaligenes Paenakaligenes cteria hominis Bordella Bordella pertussis Burkholderiaceae Burkholderia Burkholderia ma/lei, Burkholderia pseudomallei Ralstonia Ralstonia solanacea rum Neisseriaceae Neisseria Neisseria meningitidis Sutterellaceae Sutterella Sutterella parvirubra, Sutterella stercoricanis, Sutterella wadsworthensis Closfridia Clostridia/es Catabacteriaceae Catabacter Catabacter hongkongensis Clostridiaceae Aminiphila Anaerosphaera aminiphila Christensenellaceae C. massiliensis,C.
minuta, C.timonensis Hungatella Hungatella effluvia Eubacteriaceae Eubacterium Eubacterium contortum, Enterococcus durans, Eubacterium eligens, Eubacterium faecium Enterococcus faecalis, Enterococcus gallinarum , Eubacterium hadrum, Eubacterium ha//ii, Eubacterium limosum, Eubacterium ramulus, Eubacterium recta/c, Enterococcus villorum Lachnospiraceae Anaerostipes Anaerostipes caccae, Anaerostipes hadrus Blautia Blautia hydrogenotrophica, Blautia massiliensis, Blautia stercoris, Blautia wexlerae Catonella Catonella morbi Coprococcus Coprococcus catus, Coprococcus comes, Coprococcus eutactus Dialister Dialister invisus, Dialister micraeophilus , Dialister succinatiphilus Dorea Dorea formicigenerans, Dorea longicatena, Johnsonella Johnsonella ignava Oribacterium Oribacterium parvum, Oribacterium sinus Lachnobacterium Lachnoclosfridium Lacrimispora Lacrimispora sacchaarolytica Roseburia Roseburia hominis, seburia intestinalis Tyzzerella Tyzzerella nexilis Oscillospiraceae Oscillibacter Oscillibacter valericigenes Harryflintia Harryflinta acetispora Peptococcaceae Peptostreptococcacea Paraclosfridium Paraclosfridium benzoelyticum Peptostreptococcus Peptostreptococcus russellii Ruminococcaceae Agathobaculum sp.
Fournierella Fournierella masssiliensis Ruminococcus Ruminococcus albus, Ruminococcus bromii,Ruminococcu s callidus, Ruminococcus gnavus, Ruminococcus inulinivorans, Ruminococcus obeum, Ruminococcus torques Faecalibacterium Faecalibacterium prasusnitzii Clostridiales family Intestimonas XIII/ Incertae sedis butyriciproducens Fusobacteria Fusobacteriales Fusobacteriaceae Fusobacterium Fusobacterium nucleatum, Fusobacterium naviforme Leptofrichiaceae Leptotrichia Sneathia Gammaprote Enterobacterales Enterobacteriaceae Klebsiella Klebsiella oxytocaõ
obacteria Klebsiella pneumoniae, Klebsiella quasipneumoniae subsp.
Similipneumoniae, Escherichia Escherichia coli sfrain Nissle 1917 (Ec1V) Escherichia coli sfrain ECOR12 Escherichia coli sfrain ECOR63 Shigella Negativicutes Acidaminococcaceae Acidaminococcus Acidaminococcus fermentans, Acidaminococcus intestine Phascolarctobacteri Phascolarctobacteri um um faecium, Phascolarctobacteri um succinatutens Selenomonadaceae Selenomonas Selenomonas felix, Selemonadales incertae sedis, Selenomonas sputigena Sporomusaceae Selenomonadales Veillonellaceae Allisonella Anaeroglobus Anaeroglobus germ inatus Caecibacter Colibacter Veillonella Veillonella parvula Hegasphaera Hegasphera elsedenii, Megasphaera massiliensis, Megasphera micronuciformis Megasphaera sp Hassilibacillus Massilibaeillus massiliensis Propionispira Negativicoccus Negativicoccus succinicivornas Veil/one/la Veil/one/la dispar, Veil/one/la parvula, Veil/one/la ratti, Veil/one//a tobetsuensis Synergistales Synergistaceae Aminobacterium Aminobacterium mobile Cloacibacillus Cloacibacillus evryensis Rarimicrobium Rarimicrobium hominis Verrucomicro Verrucomicrobiales Akkermansiaceae Akkermansia Akkermansia bia mucinophila Table 2: Exemplary Bacterial Strains OTU Public DB Accession Actinobacillus actinomycetemcomitans AY362885 Actinobacillus minor ACFT01000025 Actinobacillus pleuropneumoniae NR 074857 Actinobacillus succinogenes CP000746 Actinobacillus ureae AEVG01000167 Actinobaculum massiliae AF487679 Actinobaculum schaalii AY957507 Actinobaculum sp. BA/1#101342 AY282578 Actinobaculum sp. P2P 19 P1 AY207066 Akkermansia mucimphila CP001071 Alistipes finegoldii NR 043064 Alistipes indistinctus AB490804 Alistipes onderdonkii NR 043318 Alistipes putredinis ABFK02000017 Alistipes shahii FP929032 Alistipes sp. HGB5 AENZ01000082 Alistipes sp. JC50 JF824804 Alistipes sp. RA/L4 9912 GQ140629 Anaerostipes caccae ABAX03000023 Anaerostipes sp. 3 2 56FAA ACWB01000002 Bacillus aeolius NR_025557 Bacillus aerophilus NR 042339 Bacillus aestuarii GQ980243 Bacillus akalophilus X76436 Bacillus amyloliquefaciens NR 075005 Bacillus anthracis AAEN01000020 Bacillus atrophaeus NR 075016 Bacillus badius NR_036893 Bacillus cereus ABDJ01000015 Bacillus circulans AB271747 Bacillus clausii FN397477 Bacillus coagulans DQ297928 Bacillus firmus NR 025842 Bacillus flexus NR 024691 Bacillus fordii NR 025786 Bacillus gelatini NR 025595 Bacillus halmapalus NR 026144 Bacillus halodurans AY144582 Bacillus herbersteinensis NR_042286 Bacillus horti NR_036860 Bacillus idriensis NR_043268 Bacillus lentus NR_040792 Bacillus licheniformis NC 006270 Bacillus megaterium GU252124 Bacillus nealsonii NR_044546 Bacillus niabensis NR_043334 Bacillus niacini NR_024695 Bacillus pocheonensis NR 041377 Bacillus pumilus NR 074977 Bacillus safensis JQ624766 Bacillus simplex NR 042136 Bacillus sonorensis NR_025130 Bacillus sp. 10403023 MA410403188 CAET01000089 Bacillus sp. 2 A 57 CT2 ACWD01000095 Bacillus sp. 2008724126 GU252108 Bacillus sp. 2008724139 GU252111 Bacillus sp. 7 16AIA FN397518 Bacillus sp. 9 3AIA FN397519 Bacillus sp. AP8 JX101689 Bacillus sp. B27(2008) EU362173 Bacillus sp. BT1B CT2 ACWC01000034 Bacillus sp. GB].] FJ897765 Bacillus sp. GB9 FJ897766 Bacillus sp. HU19.1 FJ897769 Bacillus sp. HU29 FJ897771 Bacillus sp. HU33.1 FJ897772 Bacillus sp. ,IC6 JF824800 Bacillus sp. oral taxon F26 HM099642 Bacillus sp. oral taxon F28 HM099650 Bacillus sp. oral taxon F79 HM099654 Bacillus sp. SRC DSF1 GU797283 Bacillus sp. SRC DSF10 GU797292 Bacillus sp. SRC DSF2 GU797284 Bacillus sp. SRC DSF6 GU797288 Bacillus sp. tc09 HQ844242 Bacillus sp. zh168 FJ851424 Bacillus sphaericus DQ286318 Bacillus sporothermodurans NR 026010 Bacillus subtilis EU627588 Bacillus thermoamylovorans NR 029151 Bacillus weihenstephanensis NR 074926 Bacteroidales bacterium ph8 JN837494 Bacteroidales genomosp. P1 AY341819 Bacteroidales genomosp. P2 oral clone MB] G13 DQ003613 Bacteroidales genomosp. P3 oral clone MB] G34 DQ003615 Bacteroidales genomosp. P4 oral cloneil4B2 G17 DQ003617 Bacteroidales genomosp. P5 oral cloneil4B2 PO4 DQ003619 Bacteroidales genomosp. P6 oral cloneil4B3 C19 DQ003634 Bacteroidales genomosp. P7 oral cloneil4B3 P19 DQ003623 Bacteroidales genomosp. P8 oral cloneil4B4 G15 DQ003626 Bacteroides acidifaciens NR 028607 Bacteroides barnesiae NR_041446 Bacteroides caccae EU136686 Bacteroides cellulosilyticus ACCH01000108 Bacteroides clarus AFBM01000011 Bacteroides coagulans AB547639 Bacteroides coprocola ABIY02000050 Bacteroides coprophilus ACBW01000012 Bacteroides dorei ABWZ01000093 Bacteroides eggerthii ACWG01000065 Bacteroides faecis GQ496624 Bacteroides finegoldii AB222699 Bacteroides fluxus AFBN01000029 Bacteroides fragilis AP006841 Bacteroides galacturonicus DQ497994 Bacteroides hekogenes CP002352 Bacteroides heparinolyticus JN867284 Bacteroides intestinalis ABIL02000006 Bacteroides massiliensis AB200226 Bacteroides nordii NR_043017 Bacteroides oleiciplenus AB547644 Bacteroides ovatus ACWHO1000036 Bacteroides pectinophilus ABVQ01000036 Bacteroides plebeius AB200218 Bacteroides pyogenes NR 041280 Bacteroides salanitronis CP002530 Bacteroides salyersiae EU136690 Bacteroides sp. 1 1 14 ACRP01000155 Bacteroides sp. 1 1 30 ADCL01000128 Bacteroides sp. 1 1 6 ACIC01000215 Bacteroides sp. 2 1 22 ACPQ01000117 Bacteroides sp. 2 1 56FAA ACWI01000065 Bacteroides sp. 2 2 4 ABZZ01000168 Bacteroides sp. 203 ACRQ01000064 Bacteroides sp. 3 1 19 ADCJ01000062 Bacteroides sp. 3 1 23 ACRS01000081 Bacteroides sp. 3 1 33FAA ACPS01000085 Bacteroides sp. 3 1 40A ACRT01000136 Bacteroides sp. 3 2 5 ACIB01000079 Bacteroides sp. 315 5 FJ848547 Bacteroides sp. 31SF15 AJ583248 Bacteroides sp. 31SF18 AJ583249 Bacteroides sp. 35AE31 AJ583244 Bacteroides sp. 35AE37 AJ583245 Bacteroides sp. 35BE34 AJ583246 Bacteroides sp. 35BE35 AJ583247 Bacteroides sp. 4136 ACTC01000133 Bacteroides sp. 4 3 47FAA ACDR02000029 Bacteroides sp. 9 1 42FAA ACAA01000096 Bacteroides sp. AR20 AF139524 Bacteroides sp. AR29 AF139525 Bacteroides sp. B2 EU722733 Bacteroides sp. D1 ACAB02000030 Bacteroides sp. D2 ACGA01000077 Bacteroides sp. D20 ACPT01000052 Bacteroides sp. D22 ADCK01000151 Bacteroides sp. F4 AB470322 Bacteroides sp. NB 8 AB 117565 Bacteroides sp. WH2 AY895180 Bacteroides sp. XB12B ANI230648 Bacteroides sp. XB44A ANI230649 Bacteroides stercoris ABFZ02000022 Bacteroides thetaiotaomicron NR_074277 Bacteroides uniformis AB050110 Bacteroides ureolyticus GQ167666 Bacteroides vulgatus CP000139 Bacteroides xylanisolvens ADKP01000087 Bacteroidetes bacterium oral taxon D27 HM099638 Bacteroidetes bacterium oral taxon F31 HM099643 Bacteroidetes bacterium oral taxon F44 HM099649 Barnesiella intestinihominis AB370251 Bifidobacteriaceae genomosp. Cl AY278612 Bifidobacterium adolescentis AAXDO2000018 Bifidobacterium angulatum ABYS02000004 Bifidobacterium animalis CP001606 Bifidobacterium bifidum ABQP01000027 Bifidobacterium breve CP002743 Bifidobacterium catenulatum ABXY01000019 Bifidobacterium dentium CP001750 Bifidobacterium gallicum ABXBO3000004 Bifidobacterium infantis AY151398 Bifidobacterium kashiwanohense AB491757 Bifidobacterium longum ABQQ01000041 Bifidobacterium pseudocatenulatum ABXX02000002 Bifidobacterium pseudolongum NR 043442 Bifidobacterium scardovii AJ307005 Bifidobacterium sp. HA/I2 AB425276 Bifidobacterium sp. HA/ILN12 JF519685 Bifidobacterium sp. H45 HM626176 Bifidobacterium sp.11/ISX5B HQ616382 Bifidobacterium sp. TA/I7 AB218972 Bifidobacterium therm ophilum DQ340557 Bifidobacterium urinalis AJ278695 Blautia coccoides AB571656 Blautia glucerasea AB588023 Blautia glucerasei AB439724 Blautia hansenii ABYU02000037 Blautia hydrogenofrophica ACBZ01000217 Blautia luti AB691576 Blautia producta AB600998 Blautia schinkii NR_026312 Blautia sp. H25 HM626178 Blautia stercoris HM626177 Blautia wexlerae EF036467 Bordetella bronchiseptica NR 025949 Bordetella holmesii AB683187 Bordetella parapertussis NR 025950 Bordetella pertussis BX640418 Borrelia afzelii ABCU01000001 Borrelia burgdorferi ABGI01000001 Borrelia crocidurae DQ057990 Borrelia duttonii NC_011229 Borrelia garinii ABJV01000001 Borrelia hermsii AY597657 Borrelia hispanica DQ057988 Borrelia persica HM161645 Borrelia recurrentis AF107367 Borrelia sp. NE49 AJ224142 Borrelia spielmanii ABKB01000002 Borrelia turicatae NC 008710 Borrelia valaisiana ABCY01000002 Bruce/la ovis NC 009504 Bruce/la sp. 83 13 ACBQ01000040 Bruce/la sp. B01 EU053207 Bruce/la suis ACBK01000034 Burkholderia ambifaria AAUZ01000009 Burkholderia cenocepacia AAHI01000060 Burkholderia cepacia NR 041719 Burkholderia ma/lei CP000547 Burkholderia multivorans NC_010086 Burkholderia oklahomensis DQ108388 Burkholderia pseudomallei CP001408 Burkholderia rhizoxinica HQ005410 Burkholderia sp. 383 CP000151 Burkholderia xenovorans U86373 Burkholderiales bacterium 1147 AD CQ01000066 Butyrivibrio crossotus ABWN01000012 Butyrivibrio fibrisolvens U41172 Chlamydia muridarum AE002160 Chlamydia psittaci NR 036864 Chlamydia trachomatis U68443 Chlamydiales bacterium NS11 JN606074 Citrobacter amalonaticus FR870441 Citrobacter braakii NR_028687 Citrobacter farmeri AF025371 Citrobacter freundii NR 028894 Citrobacter gillenii AF025367 Citrobacter koseri NC 009792 Citrobacter murliniae AF025369 Citrobacter rodentium NR_074903 Citrobacter sedlakii AF025364 Citrobacter sp. 302 ACDJ01000053 Citrobacter sp. KAISI 3 GQ468398 Citrobacter werkmanii AF025373 Citrobacter youngae ABWL02000011 Cloacibacillus evryensis GQ258966 Clostridiaceae bacterium END 2 EF451053 Clostridiaceae bacterium JC13 JF824807 Closfridiales bacterium 1 7 47FAA ABQR01000074 Closfridiales bacterium 9400853 HM587320 Closfridiales bacterium 9403326 HM587324 Closfridiales bacterium oral clone P4PA 66 P1 AY207065 Closfridiales bacterium oral taxon 093 GQ422712 Closfridiales bacterium oral taxon F32 HM099644 Closfridiales bacterium ph2 JN837487 Closfridiales bacterium SY8519 AB477431 Closfridiales genomosp. BVAB3 CP001850 Closfridiales sp. SA/14] FP929060 Closfridiales sp. SS3 4 AY305316 Closfridiales sp. SSC 2 FP929061 C/osfridium acetobutylicum NR 074511 C/osfridium aerotolerans X76163 C/osfridium aldenense NR_043680 C/osfridium aldrichii NR_026099 C/osfridium algidicarnis NR 041746 C/osfridium algidixylanolyticum NR 028726 C/osfridium aminovalericum NR_029245 Closfridium amygdalinum AY353957 C/osfridium argentinense NR 029232 C/osfridium asparagiforme ACCJO 1000522 C/osfridium baratii NR_029229 C/osfridium bartlettii ABEZ02000012 C/osfridium beijerinckii NR 074434 C/osfridium bifermentans X73437 Closfridium bolteae AB CCO2000039 C/osfridium botuhnum NCO 10723 Closfridium butyricum ABDT01000017 C/osfridium cadaveris AB542932 C/osfridium carboxidivorans FR733710 C/osfridium carnis NR_044716 C/osfridium celatum X77844 C/osfridium celerecrescens JQ246092 C/osfridium cellulosi NR_044624 Closfridium chauvoei EU106372 C/osfridium cifroniae ADLJO 1000059 C/osfridium clariflavum NR 041235 C/osfridium closfridiiformes M59089 C/osfridium closfridioforme NR 044715 C/osfridium coccoides EF025906 C/osfridium cochlearium NR_044717 C/osfridium cocleatum NR_026495 C/osfridium colicanis FJ957863 C/osfridium cohnum NR_026151 C/osfridium difficile NCO13315 C/osfridium disporicum NR 026491 Closfridium estertheticum NR_042153 C/osfridium fa//ax NR 044714 C/osfridium favososporum X76749 C/osfridium felsineum AF270502 C/osfridiumfrigidicarnis NR 024919 C/ostridium gasigenes NR 024945 Closfridium ghonii AB542933 Closfridium glycolicum FJ384385 C/ostridium glycyrrhizinilyticum AB233029 C/ostridium haemolyticum NR 024749 C/ostridium hathewayi AY552788 Closfridium hiranonis AB023970 C/ostridium histolyticum HF558362 Closfridium hylemonae AB023973 Closfridium indolis AF028351 C/ostridium innocuum M23732 C/ostridium irregulare NR 029249 C/ostridium isatidis NR_026347 Closfridium kluyveri NR 074165 C/ostridium lactatifermentans NR 025651 C/ostridium lavalense EF564277 Closfridium leptum AJ305238 C/ostridium /imosum FR870444 Closfridium magnum X77835 C/ostridium malenominatum FR749893 Closfridium mayombei FR733682 C/ostridium methylpentosum ACECO 1000059 C/ostridium nexile X73443 C/ostridium novyi NR 074343 C/ostridium orbiscindens Y18187 C/ostridium oroticum FR749922 C/ostridium paraputrificum AB536771 C/ostridium perfringens ABDWO 1000023 C/ostridium phytofermentans NR 074652 Closfridium piliforme D14639 C/ostridium putrefaciens NR 024995 Closfridium quinii NR 026149 C/ostridium ramosum M23731 C/ostridium rectum NR_029271 C/ostridium saccharogumia DQ100445 C/ostridium saccharolyticum CP002109 Clostridium sardiniense NR_041006 C/ostridium sartagoforme NR 026490 Closfridium scindens AF262238 C/ostridium septicum NR 026020 C/ostridium sordellii AB448946 C/ostridium sp. 7 2 43FAA ACDKO 1000101 Closfridium sp. D5 ADBG01000142 Closfridium sp. HGF2 AENW01000022 C/osfridium sp. HPB 46 AY862516 C/osfridium sp. ,IC122 CAEV01000127 Clostridium sp. L250 AAYWO2000018 Closfridium sp. DWG 16094 X95274 Clostridium sp. M62] ACFX02000046 Closfridium sp. IVILG055 AF304435 Closfridium sp. il/IT4 E FJ159523 Closfridium sp. NA/IBHI 1 JNO93130 C/osfridium sp. NAIL 04A032 EU815224 C/osfridium sp. SS2 1 AB GC03000041 Closfridium sp. SY8519 AP012212 C/osfridium sp. TM 4O AB249652 Closfridium sp. YIT 12069 AB491207 Closfridium sp. YIT 12070 AB491208 Clostridium sphenoides X73449 C/osfridium spiroforme X73441 Clostridium sporogenes ABKW02000003 C/osfridium sporosphaeroides NR 044835 C/osfridium stercorarium NR_025100 C/osfridium sticklandii L04167 C/osfridium sframinisolvens NR_024829 C/osfridium subterminale NR_041795 C/osfridium sulfidigenes NR 044161 C/osfridium symbiosum ADLQ01000114 C/osfridium tertium Y18174 C/osfridium tetani NC 004557 C/osfridium thermocellum NR_074629 C/osfridium tyrobutyricum NR 044718 C/osfridium viride NR_026204 C/osfridium xylanolyticum NR 037068 Collinsella aerofaciens AAVN02000007 Collinsella intestinalis ABXH02000037 Collinsella stercoris ABXJ01000150 Collinsella tanakaei AB490807 Coprobacillus cateniformis AB030218 Coprobacillus sp. 291 ADKX01000057 Coprobacillus sp. D7 ACDT01000199 Coprococcus catus EU266552 Coprococcus comes AB VR01000038 Coprococcus eutactus EF031543 Coprococcus sp. ART55 1 AY350746 Dialister invisus ACIM02000001 Dialister micraerophilus AFBB01000028 Dialister microaerophilus AENT01000008 Dialister pneumosintes HM596297 Dialister propionicifaciens NR 043231 Dialister sp. oral taxon 502 GQ422739 Dialister succinatiphilus AB370249 Dorea formicigenerans AAXA02000006 Dorea longicatena AJ132842 Enhydrobacter aerosaccus ACYI01000081 Enterobacter aerogenes AJ251468 Enterobacter asburiae NR_024640 Enterobacter cancerogenus Z96078 Enterobacter cloacae FP929040 Enterobacter cowanii NR_025566 Enterobacter hormaechei AFHR01000079 Enterobacter sp. 247BA/IC HQ122932 Enterobacter sp. 638 NR 074777 Enterobacter sp. JC163 JN657217 Enterobacter sp. SCSS HM007811 Enterobacter sp. TSE38 HM156134 Enterobacteriaceae bacterium 9 2 54FAA ADCU01000033 Enterobacteriaceae bacterium CFOlEnt 1 AJ489826 Enterobacteriaceae bacterium Smarlab 3302238 AY538694 Enterococcus avium AF133535 Enterococcus caccae AY943820 Enterococcus casseliflavus AEWT01000047 Enterococcus durans AJ276354 Enterococcus faecalis AE016830 Enterococcus faecium ANI157434 Enterococcus gallinarum AB269767 Enterococcus gilvus AY033814 Enterococcus hawaiiensis AY321377 Enterococcus hirae AF061011 Enterococcus italicus AEPV01000109 Enterococcus mundtii NR_024906 Enterococcus raffinosus FN600541 Enterococcus sp. BV2CASA2 JN809766 Enterococcus sp. CCRI 16620 GU457263 Enterococcus sp. F95 FJ463817 Enterococcus sp. R11,6 AJ133478 Enterococcus thailandicus AY321376 Erysipelotrichaceae bacterium 3153 ACTJ01000113 Erysipelotrichaceae bacterium 5 2 54FAA ACZW01000054 Escherichia albertii ABKX01000012 Escherichia coli NC 008563 Escherichia fergusonii CU928158 Escherichia hermannii HQ407266 Escherichia sp. 1143 ACID01000033 Escherichia sp. 4 1 40B ACDM02000056 Escherichia sp. B4 EU722735 Escherichia vulneris NR_041927 Eubacteriaceae bacterium P4P 50 P4 AY207060 Eubacterium barkeri NR_044661 Eubacterium biforme ABYT01000002 Eubacterium brachy U13038 Eubacterium budayi NR 024682 Eubacterium callanderi NR_026330 Eubacterium cellulosolvens AY178842 Eubacterium contortum FR749946 Eubacterium coprostanoligenes HM037995 Eubacterium cylindroides FP929041 Eubacterium desmolans NR_044644 Eubacterium dolichum L34682 Eubacterium eligens CP001104 Eubacterium fissicatena FR749935 Eubacterium hadrum FR749933 Eubacterium hallii L34621 Eubacterium infirmum U13039 Eubacterium limosum CP002273 Eubacterium moniliforme HF558373 Eubacterium multiforme NR 024683 Eubacterium nifritogenes NR 024684 Eubacterium nodatum U13041 Eubacterium ramulus AJ011522 Eubacterium rectale FP929042 Eubacterium ruminantium NR_024661 Eubacterium saburreum AB525414 Eubacterium saphenum NR 026031 Eubacterium siraeum AB CA03000054 Eubacterium sp. 3131 ACTL01000045 Eubacterium sp. AS15b HQ616364 Eubacterium sp. OBRC9 HQ616354 Eubacterium sp. oral clone GI038 AY349374 Eubacterium sp. oral clone IR009 AY349376 Eubacterium sp. oral clone ,IH012 AY349373 Eubacterium sp. oral clone ,11012 AY349379 Eubacterium sp. oral clone ,L11088 AY349377 Eubacterium sp. oral clone JS001 AY349378 Eubacterium sp. oral clone OH3A AY947497 Eubacterium sp. WAL 14571 FJ687606 Eubacterium tenue M59118 Eubacterium tortuosum NR_044648 Eubacterium venfriosum L34421 Eubacterium xylanophilum L34628 Eubacterium yurii AEES01000073 Fusobacterium canifelinum AY162222 Fusobacterium genomosp. Cl AY278616 Fusobacterium genomosp. C2 AY278617 Fusobacterium gonidiaformans ACET01000043 Fusobacterium mortiferum ACDB02000034 Fusobacterium naviforme HQ223106 Fusobacterium necrogenes X55408 Fusobacterium necrophorum ANI905356 Fusobacterium nucleatum ADVK01000034 Fusobacterium periodonticum ACJY01000002 Fusobacterium russii NR_044687 Fusobacterium sp. 1 1 41FAA ADGG01000053 Fusobacterium sp. 1132 ACU001000052 Fusobacterium sp. ]2]B AGWJ01000070 Fusobacterium sp. 2 1 31 ACDCO2000018 Fusobacterium sp. 3127 ADGF01000045 Fusobacterium sp. 3133 ACQE01000178 Fusobacterium sp. 3 1 36A2 ACPU01000044 Fusobacterium sp. 3 1 5R ACDD01000078 Fusobacterium sp. AC18 HQ616357 Fusobacterium sp. ACB2 HQ616358 Fusobacterium sp. AS2 HQ616361 Fusobacterium sp. CM] HQ616371 Fusobacterium sp. CA/121 HQ616375 Fusobacterium sp. CA/I22 HQ616376 Fusobacterium sp. D12 ACDG02000036 Fusobacterium sp. oral clone ASCF06 AY923141 Fusobacterium sp. oral clone ASCF11 AY953256 Fusobacterium ukerans ACDH01000090 Fusobacterium varium ACIE01000009 Gemella haemolysans ACDZ02000012 Gemella morbillorum NR_025904 Gemella morbillorum ACRX01000010 Gemella sanguinis ACRY01000057 Gemella sp. oral clone ASCE02 AY923133 Gemella sp. oral clone ASCF04 AY923139 Gemella sp. oral clone ASCF12 AY923143 Gemella sp. WAL 1945J EU427463 Klebsiella oxytoca AY292871 Klebsiella pneumoniae CP000647 Klebsiella sp. AS10 HQ616362 Klebsiella sp. Co9935 DQ068764 Klebsiella sp. enrichment culture clone SRC DSD25 HM195210 Klebsiella sp. OBRC7 HQ616353 Klebsiella sp. SP BA FJ999767 Klebsiella sp. SRC DSD1 GU797254 Klebsiella sp. SRC DSD11 GU797263 Klebsiella sp. SRC DSD12 GU797264 Klebsiella sp. SRC DSD15 GU797267 Klebsiella sp. SRC DSD2 GU797253 Klebsiella sp. SRC DSD6 GU797258 Klebsiella variicola CP001891 Lachnobacterium bovis GU324407 Lachnospira multipara FR733699 Lachnospira pectinoschiza L14675 Lachnospiraceae bacterium 1 1 57FAA ACTM01000065 Lachnospiraceae bacterium 1 4 56FAA ACTN01000028 Lachnospiraceae bacterium 2 1 46FAA ADLB01000035 Lachnospiraceae bacterium 2 1 58FAA ACT001000052 Lachnospiraceae bacterium 3 1 57FAA CT1 ACTP01000124 Lachnospiraceae bacterium 4 1 37FAA AD CR01000030 Lachnospiraceae bacterium 5 1 57FAA ACTR01000020 Lachnospiraceae bacterium 5 1 63FAA ACT SO1000081 Lachnospiraceae bacterium 6 1 63FAA ACTV01000014 Lachnospiraceae bacterium 8 1 57FAA ACWQ01000079 Lachnospiraceae bacterium 9 1 43BFAA ACTX01000023 Lachnospiraceae bacterium A4 DQ789118 Lachnospiraceae bacterium DJF VP30 EU728771 Lachnospiraceae bacterium ICA/162 HQ616401 Lachnospiraceae bacteriumil/ISX33 HQ616384 Lachnospiraceae bacterium oral taxon 107 ADD SO1000069 Lachnospiraceae bacterium oral taxon F15 HM099641 Lachnospiraceae genomosp. Cl AY278618 Lactobacillus acidipiscis NR 024718 Lactobacillus acidophilus CP000033 Lactobacillus alimentarius NR_044701 Lactobacillus amylolyticus ADNY01000006 Lactobacillus amylovorus CP002338 Lactobacillus antri ACLL01000037 Lactobacillus brevis EU194349 Lactobacillus buchneri ACGH01000101 Lactobacillus casei CP000423 Lactobacillus catenaformis M23729 Lactobacillus coleohominis ACOH01000030 Lactobacillus coryniformis NR 044705 Lactobacillus crispatus ACOG01000151 Lactobacillus curvatus NR_042437 Lactobacillus delbrueckii CP002341 Lactobacillus dextrinicus NR_036861 Lactobacillus farciminis NR 044707 Lactobacillus fermentum CP002033 Lactobacillus gasseri ACOZ01000018 Lactobacillus gastricus AICNO1000060 Lactobacillus genomosp. C] AY278619 Lactobacillus genomosp. C2 AY278620 Lactobacillus helveticus ACLM01000202 Lactobacillus hilgardii ACGP01000200 Lactobacillus hominis FR681902 Lactobacillus iners AEKJ01000002 Lactobacillus jensenii ACQD01000066 Lactobacillus johnsonii AE017198 Lactobacillus kalixensis NR_029083 Lactobacillus kefiranofaciens NR 042440 Lactobacillus kefiri NR 042230 Lactobacillus kimchii NR_025045 Lactobacillus leichmannii JX986966 Lactobacillus mucosae FR693800 Lactobacillus murinus NR_042231 Lactobacillus nodensis NR_041629 Lactobacillus oeni NR_043095 Lactobacillus oris AEKL01000077 Lactobacillus parabrevis NR 042456 Lactobacillus parabuchneri NR 041294 Lactobacillus paracasei ABQV01000067 Lactobacillus parakefiri NR 029039 Lactobacillus pentosus JN813103 Lactobacillus perolens NR 029360 Lactobacillus plantarum ACGZ02000033 Lactobacillus pontis HM218420 Lactobacillus reuteri ACGW02000012 Lactobacillus rhamnosus ABWJ01000068 Lactobacillus rogosae GU269544 Lactobacillus ruminis ACGS02000043 Lactobacillus sakei DQ989236 Lactobacillus salivarius AEBA01000145 Lactobacillus saniviri AB602569 Lactobacillus senioris AB602570 Lactobacillus sp. 66c FR681900 Lactobacillus sp. BT6 HQ616370 Lactobacillus sp. KLDS 1.0701 EU600905 Lactobacillus sp. KLDS 1.0702 EU600906 Lactobacillus sp. KLDS 1.0703 EU600907 Lactobacillus sp. KLDS 1.0704 EU600908 Lactobacillus sp. KLDS 1.0705 EU600909 Lactobacillus sp. KLDS 1.0707 EU600911 Lactobacillus sp. KLDS 1.0709 EU600913 Lactobacillus sp. KLDS 1.0711 EU600915 Lactobacillus sp. KLDS 1.0712 EU600916 Lactobacillus sp. KLDS 1.0713 EU600917 Lactobacillus sp. KLDS 1.0716 EU600921 Lactobacillus sp. KLDS 1.0718 EU600922 Lactobacillus sp. KLDS 1.0719 EU600923 Lactobacillus sp. oral clone HT002 AY349382 Lactobacillus sp. oral clone HT070 AY349383 Lactobacillus sp. oral taxon 052 GQ422710 Lactobacillus tucceti NR_042194 Lactobacillus ultunensis ACGU01000081 Lactobacillus vaginalis ACGV01000168 Lactobacillus vini NR_042196 Lactobacillus vitulinus NR_041305 Lactobacillus zeae NR_037122 Lactococcus garvieae AF061005 Lactococcus lactis CP002365 Lactococcus raffinolactis NR 044359 Listeria grayi ACCR02000003 Listeria innocua JF967625 Listeria ivanovii X56151 Listeria monocytogenes CP002003 Listeria welshimeri ANI263198 Megasphaera elsdenii AY038996 Megasphaera genomosp. C] AY278622 Megasphaera genomosp. type] ADGP01000010 Megasphaera micronuciformis AECS01000020 Megasphaera sp. BLPYG 07 HM990964 Megasphaera sp. UPII 199 6 AFIJ01000040 Microbacterium gubbeenense NR 025098 Microbacterium lacticum EU714351 Mitsuokella jalaludinii NR 028840 Mitsuokella multacida ABWK02000005 Mitsuokella sp. oral taxon 521 GU413658 Mitsuokella sp. oral taxon G68 GU432166 Mycobacterium abscessus AGQUO1000002 Mycobacterium africanum AF480605 Mycobacterium alsiensis AJ938I69 Mycobacterium avium CP000479 Mycobacterium chelonae AB548610 Mycobacterium colombiense ANI062764 Mycobacterium elephantis AF385898 Mycobacterium gordonae GU142930 Mycobacterium infracellulare GQ153276 Mycobacterium kansasii AF480601 Mycobacterium lacus NR 025175 Mycobacterium leprae FM211192 Mycobacterium lepromatosis EU203590 Mycobacterium mageritense FR798914 Mycobacterium mantenii FJ042897 Mycobacterium marinum NCO10612 Mycobacterium microti NR 025234 Mycobacterium neoaurum AF268445 Mycobacterium parascrofulaceum ADNV01000350 Mycobacterium paraterrae EU919229 Mycobacterium phlei GU142920 Mycobacterium seoulense DQ536403 Mycobacterium smegmatis CP000480 Mycobacterium sp. 1761 EU703150 Mycobacterium sp. 1776 EU703152 Mycobacterium sp. 1781 EU703147 Mycobacterium sp. 1791 EU703148 Mycobacterium sp. 1797 EU703149 Mycobacterium sp. AQ1GA4 HM210417 Mycobacterium sp. B10 07.09.0206 HQ174245 Mycobacterium sp. GN 10546 FJ497243 Mycobacterium sp. GN 10827 FJ497247 Mycobacterium sp. GN 11124 FJ652846 Mycobacterium sp. GN 9188 FJ497240 Mycobacterium sp. GR 2007 210 FJ555538 Mycobacterium sp. HE5 AJ012738 Mycobacterium sp. NLA001000736 HM627011 Mycobacterium sp. W DQ437715 Mycobacterium tuberculosis CP001658 Mycobacterium ukerans AB548725 Mycobacterium vulneris EU834055 Mycoplasma agalactiae AF010477 Mycoplasma amphoriforme AY531656 Mycoplasma arthritidis NCO11025 Mycoplasma bovoculi NR 025987 Mycoplasma faucium NR 024983 Mycoplasma fermentans CP002458 Mycoplasma flocculare X62699 Mycoplasma genitalium L43967 Mycoplasma hominis AF443616 Mycoplasma orale AY796060 Mycoplasma ovipneumoniae NR 025989 Mycoplasma penetrans NC 004432 Mycoplasma pneumoniae NC 000912 Mycoplasma putrefaciens U26055 Mycoplasma salivarium M24661 Mycoplasmataceae genomosp. P1 oral clone MB] G23 DQ003614 Neisseria bacilliformis AFAY01000058 Neisseria cinerea ACDY01000037 Neisseria elongata ADBF01000003 Neisseria flavescens ACQV01000025 Neisseria genomosp. P2 oral clone A/IBS P15 DQ003630 Neisseria gonorrhoeae CP002440 Neisseria lactamica ACEQ01000095 Neisseria macacae AFQE01000146 Neisseria meningitidis NC 003112 Neisseria mucosa ACDX01000110 Neisseria pharyngis AJ239281 Neisseria polysaccharea ADBE01000137 Neisseria sicca ACK002000016 Neisseria sp. KEA/I232 GQ203291 Neisseria sp. oral clone AP132 AY005027 Neisseria sp. oral clone JC012 AY349388 Neisseria sp. oral strain B33KA AY005028 Neisseria sp. oral taxon 014 ADEA01000039 Neisseria sp. SMC A9199 FJ763637 Neisseria sp. TA/110 1 DQ279352 Neisseria subflava ACE001000067 Odoribacter laneus AB490805 Odoribacter splanchnicus CP002544 Oscillibacter sp. G2 HM626173 Oscillibacter valericigenes NR 074793 Oscillospira guilliermondii AB040495 Paenibacillus barcinonensis NR_042272 Paenibacillus barengoltzii NR 042756 Paenibacillus chibensis NR_040885 Paenibacillus cookii NR_025372 Paenibacillus durus NR_037017 Paenibacillus glucanolyticus D78470 Paenibacillus lactis NR_025739 Paenibacillus lautus NR_040882 Paenibacillus pabuli NR 040853 Paenibacillus polymyxa NR 037006 Paenibacillus popilliae NR 040888 Paenibacillus sp. CIP 101062 HM212646 Parabacteroides distasonis CP000140 Parabacteroides goldsteinii AY974070 Parabacteroides gordonii AB470344 Parabacteroides johnsonii ABYHO1000014 Parabacteroides merdae EU136685 Parabacteroides sp. D13 ACPW01000017 Parabacteroides sp. NS31 3 JN029805 Peptococcus niger NR 029221 Peptococcus sp. oral clone ,1114048 AY349389 Peptococcus sp. oral taxon 167 GQ422727 Peptoniphilus asaccharolyticus D14145 Peptoniphilus duerdenii EU526290 Peptoniphilus harei NR 026358 Peptoniphilus indolicus AY153431 Peptoniphilus ivorii Y07840 Peptoniphilus lacrimalis ADD001000050 Peptoniphilus sp. gpac007 ANI176517 Peptoniphilus sp. gpac018A ANI176519 Peptoniphilus sp. gpac077 ANI176527 Peptoniphilus sp. gpac148 ANI176535 Peptoniphilus sp. ,IC140 JF824803 Peptoniphilus sp. oral taxon 386 AD CS01000031 Peptoniphilus sp. oral taxon 836 AEAA01000090 Peptosfreptococcaceae bacterium ph] JN837495 Peptosfreptococcus anaerobius AY326462 Peptosfreptococcus micros ANI176538 Peptosfreptococcus sp. 9succl X90471 Peptosfreptococcus sp. oral clone AP24 AB 175072 Peptosfreptococcus sp. oral clone FJ023 AY349390 Peptosfreptococcus sp. P4P 31 P3 AY207059 Peptosfreptococcus stomatis AD GQ01000048 Porphyromonadaceae bacterium NAIL 060648 EF184292 Porphyromonas asaccharolytica AEN001000048 Porphyromonas endodontalis ACNN01000021 Porphyromonas gingivalis AE015924 Porphyromonas levii NR 025907 Porphyromonas macacae NR 025908 Porphyromonas somerae AB547667 Porphyromonas sp. oral clone BB134 AY005068 Porphyromonas sp. oral clone F016 AY005069 Porphyromonas sp. oral clone P2PB 52 P1 AY207054 Porphyromonas sp. oral clone P4GB 100 P2 AY207057 Porphyromonas sp. UQD 301 EU012301 Porphyromonas uenonis ACLR01000152 Prevotella albensis NR_025300 Prevotella amnii AB547670 Prevotella bergensis ACKS01000100 Prevotella bivia ADF001000096 Prevotella brevis NR_041954 Prevotella buccae ACRB01000001 Prevotella buccalis JN86726I
Prevotella copri ACBX02000014 Prevotella corporis L16465 Prevotella dentalis AB547678 Prevotella denticola CP002589 Prevotella disiens AED001000026 Prevotella genomosp. Cl AY278624 Prevotella genomosp. C2 AY278625 Prevotella genomosp. P7 oral clone 11/1B2 P31 DQ003620 Prevotella genomosp. P8 oral clone 11/1B3 P13 DQ003622 Prevotella genomosp. P9 oral clone 11/1B7 G16 DQ003633 Prevotella heparinolytica GQ422742 Prevotella histicola JN867315 Prevotella intermedia AF414829 Prevotella loescheii JN86723I
Prevotella maculosa AGEK01000035 Prevotella marshii AEEI01000070 Prevotella melaninogenica CP002122 Prevotella micans AGWK01000061 Prevotella multiformis AEWX01000054 Prevotella multisaccharivorax AFJE01000016 Prevotella nanceiensis JN867228 Prevotella nigrescens AFPX01000069 Prevotella oralis AEPE01000021 Prevotella oris ADD V01000091 Prevotella oulorum L16472 Prevotella pal/ens AFPY01000135 Prevotella ruminicola CP002006 Prevotella salivae AB 108826 Prevotella sp. B142 AJ581354 Prevotella sp. CA438 HQ610181 Prevotella sp. ICAll HQ616385 Prevotella sp. ICA455 HQ616399 Prevotella sp. KM 6330 AB547699 Prevotella sp. oral clone AA020 AY005057 Prevotella sp. oral clone ASCG10 AY923148 Prevotella sp. oral clone ASCG12 DQ272511 Prevotella sp. oral clone AU069 AY005062 Prevotella sp. oral clone CY006 AY005063 Prevotella sp. oral clone DA058 AY005065 Prevotella sp. oral clone FLO19 AY349392 Prevotella sp. oral clone FU048 AY349393 Prevotella sp. oral clone FW035 AY349394 Prevotella sp. oral clone GI030 AY349395 Prevotella sp. oral clone GI032 AY349396 Prevotella sp. oral clone GI059 AY349397 Prevotella sp. oral clone GU027 AY349398 Prevotella sp. oral clone HF050 AY349399 Prevotella sp. oral clone ID019 AY349400 Prevotella sp. oral clone IDR CEC 0055 AY550997 Prevotella sp. oral clone IK053 AY349401 Prevotella sp. oral clone IK062 AY349402 Prevotella sp. oral clone P4PB 83 P2 AY207050 Prevotella sp. oral taxon 292 GQ422735 Prevotella sp. oral taxon 299 ACWZ01000026 Prevotella sp. oral taxon 300 GU409549 Prevotella sp. oral taxon 302 ACZKO1000043 Prevotella sp. oral taxon 310 GQ422737 Prevotella sp. oral taxon 317 ACQH01000158 Prevotella sp. oral taxon 472 ACZ SO1000106 Prevotella sp. oral taxon 781 GQ422744 Prevotella sp. oral taxon 782 GQ422745 Prevotella sp. oral taxon F68 HM099652 Prevotella sp. oral taxon G60 GU432133 Prevotella sp. oral taxon G70 GU432179 Prevotella sp. oral taxon G71 GU432180 Prevotella sp. SEQ053 JN867222 Prevotella sp. SEQ065 JN867234 Prevotella sp. SEQ072 JN867238 Prevotella sp. SEQ116 JN867246 Prevotella sp. SG12 GU561343 Prevotella sp. sp24 AB003384 Prevotella sp. sp34 AB003385 Prevotella stercorea AB244774 Prevotella tannerae ACIJ02000018 Prevotella timonensis ADEF01000012 Prevotella veroralis ACVA01000027 Prevotellaceae bacterium P4P 62 P1 AY207061 Propionibacteriaceae bacterium NAIL 02 0265 EF599122 Propionibacterium acidipropionici NCO19395 Propionibacterium acnes ADJM01000010 Propionibacterium avidum AJ003055 Propionibacterium freudenreichii NR 036972 Propionibacterium granulosum FJ785716 Propionibacterium jensenii NR 042269 Propionibacterium propionicum NR 025277 Propionibacterium sp. 434 HC2 AFIL01000035 Propionibacterium sp. H456 AB177643 Propionibacterium sp. LG AY354921 Propionibacterium sp. oral taxon 192 GQ422728 Propionibacterium sp. S555a AB264622 Propionibacterium thoenii NR 042270 Pseudomonas aeruginosa AABQ07000001 Pseudomonas fluorescens AY622220 Pseudomonas gessardii FJ943496 Pseudomonas mendocina AAUL01000021 Pseudomonas monteilii NR_024910 Pseudomonas poae GU188951 Pseudomonas pseudoalcaligenes NR 037000 Pseudomonas putida AF094741 Pseudomonas sp. 2126 ACWU01000257 Pseudomonas sp. G1229 DQ910482 Pseudomonas sp. NP522b EU723211 Pseudomonas stutzeri ANI905854 Pseudomonas tolaasii AF320988 Pseudomonas viridiflava NR 042764 Ralstonia pickettii NCO10682 Ralstonia sp. 5 7 47FAA ACUF01000076 Roseburia cecicola GU233441 Roseburia faecalis AY804149 Roseburia faecis AY305310 Roseburia hominis AJ270482 Roseburia intestinalis FP929050 Roseburia inulinivorans AJ270473 Roseburia sp. 11SE37 FM954975 Roseburia sp. 11SE38 FM954976 Rothia aeria DQ673320 Rothia dentocariosa ADD W01000024 Rothia mucilaginosa ACV001000020 Rothia nasimurium NR_025310 Rothia sp. oral taxon 188 GU470892 Ruminobacter amylophilus NR 026450 Ruminococcaceae bacterium D16 ADDX01000083 Ruminococcus albus AY445600 Ruminococcus bromii EU266549 Ruminococcus callidus NR_029160 Ruminococcus champanellensis FP929052 Ruminococcus flavefaciens NR 025931 Ruminococcus gnavus X94967 Ruminococcus hansenii M59114 Ruminococcus lactaris AB0U02000049 Ruminococcus obeum AY169419 Ruminococcus sp. 18P13 AJ515913 Ruminococcus sp. 5 1 39BFAA ACI101000172 Ruminococcus sp. 9SE51 FM954974 Ruminococcus sp. ID8 AY960564 Ruminococcus sp. K] AB222208 Ruminococcus torques AAVP02000002 Salmonella bongori NR 041699 Salmonella enterica NC 011149 Salmonella enterica NC_011205 Salmonella enterica DQ344532 Salmonella enterica ABEH02000004 Salmonella enterica ABAK02000001 Salmonella enterica NC_011080 Salmonella enterica EU118094 Salmonella enterica NC_011094 Salmonella enterica AE014613 Salmonella enterica ABFH02000001 Salmonella enterica ABEM01000001 Salmonella enterica ABANI02000001 Salmonella typhimurium DQ344533 Salmonella typhimurium AF170176 Selenomonas artemidis HM596274 Selenomonas dianae GQ422719 Selenomonas flueggei AF287803 Selenomonas genomosp. Cl AY278627 Selenomonas genomosp. C2 AY278628 Selenomonas genomosp. P5 AY341820 Selenomonas genomosp. P6 oral cloneMB3 C41 DQ003636 Selenomonas genomosp. P7 oral cloneil/IB5 CO8 DQ003627 Selenomonas genomosp. P8 oral cloneil/IB5 PO6 DQ003628 Selenomonas infelix AF287802 Selenomonas noxia GU470909 Selenomonas ruminantium NR_075026 Selenomonas sp. FOBRC9 HQ616378 Selenomonas sp. oral clone FT050 AY349403 Selenomonas sp. oral clone G1064 AY349404 Selenomonas sp. oral clone GT010 AY349405 Selenomonas sp. oral clone HU051 AY349406 Selenomonas sp. oral clone IK004 AY349407 Selenomonas sp. oral clone IQ048 AY349408 Selenomonas sp. oral clone ,11021 AY349409 Selenomonas sp. oral clone ,I5031 AY349410 Selenomonas sp. oral clone OH4A AY947498 Selenomonas sp. oral clone P2PA 80 P4 AY207052 Selenomonas sp. oral taxon 137 AENV01000007 Selenomonas sp. oral taxon 149 AEEJ01000007 Selenomonas sputigena ACKP02000033 Serratia fonticola NR 025339 Serratia liquefaciens NR 042062 Serratia marcescens GU826157 Serratia odorifera ADBY01000001 Serratia proteamaculans AAUN01000015 Shigella boydii AAKA01000007 Shigella dysenteriae NC 007606 Shigella flexneri AE005674 Shigella sonnei NC 007384 Sphingobacterium faecium NR 025537 Sphingobacterium mizutaii JF708889 Sphingobacterium multivorum NR 040953 Sphingobacterium spiritivorum ACHA02000013 Sphingomonas echinoides NR 024700 Sphingomonas sp. oral clone F1012 AY349411 Sphingomonas sp. oral clone FZ016 AY349412 Sphingomonas sp. oral taxon A09 HM099639 Sphingomonas sp. oral taxon F71 HM099645 Staphylococcaceae bacterium NAIL 92 0017 AY841362 Staphylococcus aureus CP002643 Staphylococcus auricularis JQ624774 Staphylococcus capitis ACFRO1000029 Staphylococcus caprae ACRH01000033 Staphylococcus carnosus NR 075003 Staphylococcus cohnii JN175375 Staphylococcus condimenti NR 029345 Staphylococcus epidermidis ACHE01000056 Staphylococcus equorum NR 027520 Staphylococcus fleurettii NR 041326 Staphylococcus haemolyticus NC 007168 Staphylococcus hominis ANI157418 Staphylococcus lugdunensis AEQA01000024 Staphylococcus pasteuri FJ189773 Staphylococcus pseudintermedius CP002439 Staphylococcus saccharolyticus NR 029158 Staphylococcus saprophyticus NC 007350 Staphylococcus sciuri NR 025520 Staphylococcus sp. clone bottae7 AF467424 Staphylococcus sp. H292 AB177642 Staphylococcus sp. H780 AB177644 Staphylococcus succinus NR 028667 Staphylococcus vitulinus NR 024670 Staphylococcus warneri ACPZ01000009 Staphylococcus xylosus AY395016 Strepto bacillus moniliformis NR 027615 Sfreptococcus agalactiae AAJ001000130 Sfreptococcus alactolyticus NR 041781 Sfreptococcus anginosus AECT01000011 Sfreptococcus ausfralis AEQR01000024 Sfreptococcus bovis AEEL01000030 Sfreptococcus canis AJ413203 Sfreptococcus constellatus AY277942 Sfreptococcus cristatus AEVC01000028 Sfreptococcus downei AEKNO1000002 Sfreptococcus dysgalactiae AP010935 Sfreptococcus equi CP001129 Sfreptococcus equinus AEVB01000043 Sfreptococcus gallolyticus FR824043 Sfreptococcus genomosp. Cl AY278629 Sfreptococcus genomosp. C2 AY278630 Sfreptococcus genomosp. C3 AY278631 Sfreptococcus genomosp. C4 AY278632 Sfreptococcus genomosp. C5 AY278633 Sfreptococcus genomosp. C6 AY278634 Sfreptococcus genomosp. C7 AY278635 Sfreptococcus genomosp. C8 AY278609 Sfreptococcus gordonii NC 009785 Sfreptococcus infantarius ABJK02000017 Sfreptococcus infantis AFNN01000024 Sfreptococcus intermedius NR 028736 Sfreptococcus lutetiensis NR 037096 Streptococcus massiliensis AY769997 Streptococcus miller X81023 Streptococcus mitis ANI157420 Sfreptococcus mutans AP010655 Sfreptococcus oligofermentans AY099095 Sfreptococcus oralis ADMV01000001 Sfreptococcus parasanguinis AEKNIO 1000012 Sfreptococcus pasteurianus AP012054 Sfreptococcus peroris AEVF01000016 Sfreptococcus pneumoniae AE008537 Sfreptococcus porcinus EF121439 Sfreptococcus pseudopneumoniae FJ827123 Sfreptococcus pseudoporcinus AENS01000003 Sfreptococcus pyogenes AE006496 Streptococcus ratti X58304 Sfreptococcus salivarius AGBV01000001 Sfreptococcus sanguinis NR 074974 Sfreptococcus sinensis AF432857 Streptococcus sp. 16362 JN590019 Streptococcus sp. 2 1 36FAA ACOI01000028 Streptococcus sp. 2285 97 AJ131965 Streptococcus sp. 69130 X78825 Sfreptococcus sp. AC15 HQ616356 Sfreptococcus sp. ACS2 HQ616360 Streptococcus sp. A520 HQ616366 Sfreptococcus sp. BS35a HQ616369 Sfreptococcus sp. C150 ACRI01000045 Sfreptococcus sp. CA/I6 HQ616372 Sfreptococcus sp. CA/I7 HQ616373 Sfreptococcus sp. ICAll 0 HQ616389 Sfreptococcus sp. ICA/I12 HQ616390 Sfreptococcus sp. ICA/I2 HQ616386 Sfreptococcus sp. ICA/I4 HQ616387 Sfreptococcus sp. ICA/I45 HQ616394 Streptococcus sp. A4143 ACRK01000025 Streptococcus sp. A4334 ACRL01000052 Sfreptococcus sp. OBRC6 HQ616352 Sfreptococcus sp. oral clone A5B02 AY923121 Sfreptococcus sp. oral clone ASCA03 DQ272504 Sfreptococcus sp. oral clone ASCA04 AY923116 Sfreptococcus sp. oral clone ASCA09 AY923119 Sfreptococcus sp. oral clone ASCB04 AY923123 Sfreptococcus sp. oral clone ASCB06 AY923124 Sfreptococcus sp. oral clone ASCCO4 AY923127 Sfreptococcus sp. oral clone ASCCO5 AY923128 Sfreptococcus sp. oral clone ASCC12 DQ272507 Sfreptococcus sp. oral clone ASCD01 AY923129 Sfreptococcus sp. oral clone ASCD09 AY923130 Sfreptococcus sp. oral clone ASCD10 DQ272509 Sfreptococcus sp. oral clone ASCE03 AY923134 Sfreptococcus sp. oral clone ASCE04 AY953253 Sfreptococcus sp. oral clone ASCE05 DQ272510 Sfreptococcus sp. oral clone ASCE06 AY923135 Sfreptococcus sp. oral clone ASCE09 AY923136 Sfreptococcus sp. oral clone ASCE10 AY923137 Sfreptococcus sp. oral clone ASCE12 AY923138 Sfreptococcus sp. oral clone ASCF05 AY923140 Sfreptococcus sp. oral clone ASCF07 AY953255 Sfreptococcus sp. oral clone ASCF09 AY923142 Sfreptococcus sp. oral clone ASCGO4 AY923145 Sfreptococcus sp. oral clone BW009 AY005042 Sfreptococcus sp. oral clone CH016 AY005044 Sfreptococcus sp. oral clone GK051 AY349413 Streptococcus sp. oral clone GA4006 AY349414 Sfreptococcus sp. oral clone P2PA 41 P2 AY207051 Sfreptococcus sp. oral clone P4PA 30 P4 AY207064 Sfreptococcus sp. oral taxon 071 AEEP01000019 Sfreptococcus sp. oral taxon G59 GU432132 Sfreptococcus sp. oral taxon G62 GU432146 Sfreptococcus sp. oral taxon G63 GU432150 Sfreptococcus sp. SHV515 Y07601 Sfreptococcus suis FM252032 Sfreptococcus thermophilus CP000419 Sfreptococcus uberis HQ391900 Sfreptococcus urinalis DQ303194 Sfreptococcus vestibularis AEK001000008 Sfreptococcus viridans AF076036 Sutterella morbirenis AJ832129 Sutterella parvirubra AB300989 Sutterella sanguinus AJ748647 Sutterella sp. YIT 12072 AB491210 Sutterella stercoricanis NR_025600 Sutterella wadsworthensis ADMF01000048 Synergistes genomosp. Cl AY278615 Synergistes sp. RAI4 14551 DQ412722 Synergistetes bacterium ADV897 GQ258968 Synergistetes bacterium LBVCA41157 GQ258969 Synergistetes bacterium oral taxon 362 GU410752 Synergistetes bacterium oral taxon D48 GU430992 Turicibacter sanguinis AF349724 Veillonella atypica AEDS01000059 Veillonella dispar ACIK02000021 Veillonella genomosp. P1 oral clone il/IB5 P17 DQ003631 Veillonella montpellierensis AF473836 Veillonella parvula ADFU01000009 Veillonella sp. 3144 ADCV01000019 Veillonella sp. 6127 ADCW01000016 Veillonella sp. ACP 1 HQ616359 Veillonella sp. AS16 HQ616365 Veillonella sp. BS32b HQ616368 Veillonella sp. ICA/I5 la HQ616396 Veillonella sp. IVISA12 HQ616381 Veillonella sp. NVG 100cf EF108443 Veillonella sp. OK]] JN695650 Veillonella sp. oral clone ASCA08 AY923118 Veillonella sp. oral clone ASCB03 AY923122 Veillonella sp. oral clone ASCGO1 AY923144 Veillonella sp. oral clone ASCGO2 AY953257 Veillonella sp. oral clone OH1A AY947495 Veillonella sp. oral taxon 158 AENU01000007 Veillonellaceae bacterium oral taxon 131 GU402916 Veillonellaceae bacterium oral taxon 155 GU470897 Vibrio cholerae AAUR01000095 Vibrio fluvialis X76335 Vibrio furnissii CP002377 Vibrio mimicus ADAF01000001 Vibrio parahaemolyticus AAWQ01000116 Vibrio sp. RC341 ACZT01000024 Vibrio vulnificus AE016796 Yersinia aldovae AJ871363 Yersinia aleksiciae AJ627597 Yersinia bercovieri AF366377 Yersinia enterocolitica FR729477 Yersinia frederiksenii AF366379 Yersinia intermedia AF366380 Yersinia kristensenii ACCA01000078 Yersinia mollaretii NR_027546 Yersinia pestis AE013632 Yersinia pseudotuberculosis NC 009708 Yersinia rohdei ACCD01000071 Table 3: Exemplary Bacterial Strains Strain Deposit Number Parabacteroides goldsteinii PTA-126574 Bifidobacterium animalis ssp. lactis Strain A PTA-125097 Blautia Hassiliensis Strain A PTA-125134 NRRL accession Number B
Prevotella Sfrain B

Prevotella Histicola PTA-126140 Blautia Strain A PTA-125346 Lactococcus lactis cremoris Strain A PTA-125368 Lactobacillus salivarius PTA-125893 Ruminococcus gnavus strain PTA-125706 Tyzzerella nexilis sfrain PTA-125707 Paraclosfridium benzoelyticum PTA-125894 Ruminococcus gnavus (also referred to as PTA-126695 Hediterraneibacter gnavus) Veillonella parvula PTA-125710 Veillonella atypica Strain A PTA-125709 Veillonella atypica Strain B PTA-125711 Veillonella parvula Strain A PTA-125691 Veillonella parvula Strain B PTA-125711 Veillonella tobetsuensis Strain A PTA-125708 Agathobaculum sp. PTA-125892 Turicibacter sanguinis PTA-125889 Klebsiella quasipneumoniae subsp. similipneumoniae PTA-125891 Klebsiella oxytoca PTA-125890 illegasphaera Sp. Sfrain A PTA-126770 illegasphaera Sp. PTA-126837 Harryflintia acetispora PTA-126694 Fournierella massiliensis PTA-126696 Modified Bacteria and mEVs [1533] In some aspects, the bacteria and/or mEVs (such as smEVs and/or pmEVs) described herein are modified such that they comprise, are linked to, and/or are bound by a therapeutic moiety.
[1534] In some embodiments, the therapeutic moiety is a cancer-specific moiety. In some embodiments, the cancer-specific moiety has binding specificity for a cancer cell (e.g., has binding specificity for a cancer-specific antigen). In some embodiments, the cancer-specific moiety comprises an antibody or antigen binding fragment thereof. In some embodiments, the cancer-specific moiety comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the cancer-specific moiety comprises a ligand for a receptor expressed on the surface of a cancer cell or a receptor-binding fragment thereof. In some embodiments, the cancer-specific moiety is a bipartite fusion protein that has two parts: a first part that binds to and/or is linked to the bacterium and a second part that is capable of binding to a cancer cell (e.g., by haying binding specificity for a cancer-specific antigen). In some embodiments, the first part is a fragment of or a full-length peptidoglycan recognition protein, such as PGRP. In some embodiments the first part has binding specificity for the mEV (e.g., by haying binding specificity for a bacterial antigen). In some embodiments, the first and/or second part comprises an antibody or antigen binding fragment thereof In some embodiments, the first and/or second part comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the first and/or second part comprises a ligand for a receptor expressed on the surface of a cancer cell or a receptor-binding fragment thereof In certain embodiments, co-administration of the cancer-specific moiety with the pharmaceutical agent (either in combination or in separate administrations) increases the targeting of the pharmaceutical agent to the cancer cells.
[1535] In some embodiments, the bacteria and/or mEVs described herein can be modified such that they comprise, are linked to, and/or are bound by a magnetic and/or paramagnetic moiety (e.g., a magnetic bead). In some embodiments, the magnetic and/or paramagnetic moiety is comprised by and/or directly linked to the bacteria. In some embodiments, the magnetic and/or paramagnetic moiety is linked to and/or a part of a bacteria- or an mEV-binding moiety that binds to the bacteria or mEV. In some embodiments, the bacteria- or mEV-binding moiety is a fragment of or a full-length peptidoglycan recognition protein, such as PGRP. In some embodiments the bacteria- or mEV-binding moiety has binding specificity for the bacteria or mEV (e.g., by having binding specificity for a bacterial antigen). In some embodiments, the bacteria- or mEV-binding moiety comprises an antibody or antigen binding fragment thereof In some embodiments, the bacteria- or mEV-binding moiety comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the bacteria- or mEV-binding moiety comprises a ligand for a receptor expressed on the surface of a cancer cell or a receptor-binding fragment thereof In certain embodiments, co-administration of the magnetic and/or paramagnetic moiety with the bacteria or mEVs (either together or in separate administrations) can be used to increase the targeting of the mEVs (e.g., to cancer cells and/or a part of a subject where cancer cells are present.
Production of Processed Microbial Extracellular Vesicles (pmEVs) [1536] In certain aspects, the pmEVs described herein can be prepared using any method known in the art.
[1537] In some embodiments, the pmEVs are prepared without a pmEV
purification step. For example, in some embodiments, bacteria from which the pmEVs described herein are released are killed using a method that leaves the bacterial pmEVs intact, and the resulting bacterial components, including the pmEVs, are used in the methods and compositions described herein. In some embodiments, the bacteria are killed using an antibiotic (e.g., using an antibiotic described herein). In some embodiments, the bacteria are killed using UV irradiation.
[1538] In some embodiments, the pmEVs described herein are purified from one or more other bacterial components. Methods for purifying pmEVs from bacteria (and optionally, other bacterial components) are known in the art. In some embodiments, pmEVs are prepared from bacterial cultures using methods described in Thein, et at.
(J. Proteome Res. 9(12):6135-6147 (2010)) or Sandrini, et al. (Bio-protocol 4(21): e1287 (2014)), each of which is hereby incorporated by reference in its entirety. In some embodiments, the bacteria are cultured to high optical density and then centrifuged to pellet bacteria (e.g., at 10,000- 15,000 x g for 10- 15 min at room temperature or 4 C). In some embodiments, the supernatants are discarded and cell pellets are frozen at -80 C. In some embodiments, cell pellets are thawed on ice and resuspended in 100 mM Tris-HC1, pH 7.5 supplemented with 1 mg/mL DNase I. In some embodiments, cells are lysed using an Emulsiflex C-3 (Avestin, Inc.) under conditions recommended by the manufacturer. In some embodiments, debris and unlysed cells are pelleted by centrifugation at 10,000 x g for 15 min at 4 C. In some embodiments, supernatants are then centrifuged at 120,000 x g for 1 hour at 4 C. In some embodiments, pellets are resuspended in ice-cold 100 mM sodium carbonate, pH
11, incubated with agitation for 1 hr at 4 C, and then centrifuged at 120,000 x g for 1 hour at 4 C. In some embodiments, pellets are resuspended in 100 mM Tris-HC1, pH 7.5, re-centrifuged at 120,000 x g for 20 min at 4 C, and then resuspended in 0.1 M
Tris-HC1, pH
7.5 or in PBS. In some embodiments, samples are stored at -20 C.
[1539] In certain aspects, pmEVs are obtained by methods adapted from Sandrini et al, 2014. In some embodiments, bacterial cultures are centrifuged at 10,000-15,500 x g for 10-15 min at room temp or at 4 C. In some embodiments, cell pellets are frozen at -80 C
and supernatants are discarded. In some embodiments, cell pellets are thawed on ice and resuspended in 10 mM Tris-HC1, pH 8.0, 1 mM EDTA supplemented with 0.1 mg/mL
lysozyme. In some embodiments, samples are incubated with mixing at room temp or at 37 C for 30 min. In some embodiments, samples are re-frozen at -80 C and thawed again on ice. In some embodiments, DNase I is added to a final concentration of 1.6 mg/mL and MgCl2 to a final concentration of 100 mM. In some embodiments, samples are sonicated using a QSonica Q500 sonicator with 7 cycles of 30 sec on and 30 sec off In some embodiments, debris and unlysed cells are pelleted by centrifugation at 10,000 x g for 15 min. at 4 C. In some embodiments, supernatants are then centrifuged at 110,000 x g for 15 min at 4 C. In some embodiments, pellets are resuspended in 10 mM Tris-HC1, pH
8.0, 2%
Triton X-100 and incubated 30-60 min with mixing at room temperature. In some embodiments, samples are centrifuged at 110,000 x g for 15 min at 4 C. In some embodiments, pellets are resuspended in PBS and stored at -20 C.
[1540] In certain aspects, a method of forming (e.g., preparing) isolated bacterial pmEVs, described herein, comprises the steps of: (a) centrifuging a bacterial culture, thereby forming a first pellet and a first supernatant, wherein the first pellet comprises cells;
(b) discarding the first supernatant;(c) resuspending the first pellet in a solution; (d) lysing the cells; (e) centrifuging the lysed cells, thereby forming a second pellet and a second supernatant; (f) discarding the second pellet and centrifuging the second supernatant, thereby forming a third pellet and a third supernatant; (g) discarding the third supernatant and resuspending the third pellet in a second solution, thereby forming the isolated bacterial pmEVs.

[1541] In some embodiments, the method further comprises the steps of:
(h) centrifuging the solution of step (g), thereby forming a fourth pellet and a fourth supernatant; (i) discarding the fourth supernatant and resuspending the fourth pellet in a third solution. In some embodiments, the method further comprises the steps of: (j) centrifuging the solution of step (i), thereby forming a fifth pellet and a fifth supernatant;
and (k) discarding the fifth supernatant and resuspending the fifth pellet in a fourth solution.
[1542] In some embodiments, the centrifugation of step (a) is at 10,000 x g. In some embodiments the centrifugation of step (a) is for 10-15 minutes. In some embodiments, the centrifugation of step (a) is at 4 C or room temperature. In some embodiments, step (b) further comprises freezing the first pellet at -80 C. In some embodiments, the solution in step (c) is 100mM Tris-HC1, pH 7.5 supplemented with lmg/m1DNaseI. In some embodiments, the solution in step (c) is 10mM Tris-HC1, pH 8.0, 1mM EDTA, supplemented with 0.1 mg/ml lysozyme. In some embodiments, step (c) further comprises incubating for 30 minutes at 37 C or room temperature. In some embodiments, step (c) further comprises freezing the first pellet at -80 C. In some embodiments, step (c) further comprises adding DNase Ito a final concentration of 1.6mg/ml. In some embodiments, step (c) further comprises adding MgCl2 to a final concentration of 100mM. In some embodiments, the cells are lysed in step (d) via homogenization. In some embodiments, the cells are lysed in step (d) via emulsiflex C3. In some embodiments, the cells are lysed in step (d) via sonication. In some embodiments, the cells are sonicated in 7 cycles, wherein each cycle comprises 30 seconds of sonication and 30 seconds without sonication. In some embodiments, the centrifugation of step (e) is at 10,000 x g. In some embodiments, the centrifugation of step (e) is for 15 minutes. In some embodiments, the centrifugation of step (e) is at 4 C or room temperature.
[1543] In some embodiments, the centrifugation of step (f) is at 120,000 x g. In some embodiments, the centrifugation of step (f) is at 110,000 x g. In some embodiments, the centrifugation of step (f) is for 1 hour. In some embodiments, the centrifugation of step (f) is for 15 minutes. In some embodiments, the centrifugation of step (f) is at 4 C or room temperature. In some embodiments, the second solution in step (g) is 100 mM
sodium carbonate, pH 11. In some embodiments, the second solution in step (g) is 10mM
Tris-HC1 pH 8.0, 2% triton X-100. In some embodiments, step (g) further comprises incubating the solution for 1 hour at 4 C. In some embodiments, step (g) further comprises incubating the solution for 30-60 minutes at room temperature. In some embodiments, the centrifugation of step (h) is at 120,000 x g. In some embodiments, the centrifugation of step (h) is at 110,000 x g. In some embodiments, the centrifugation of step (h) is for 1 hour. In some embodiments, the centrifugation of step (h) is for 15 minutes. In some embodiments, the centrifugation of step (h) is at 4 C or room temperature. In some embodiments, the third solution in step (i) is 100mM Tris-HC1, pH 7.5. In some embodiments, the third solution in step (i) is PBS. In some embodiments, the centrifugation of step (j) is at 120,000 x g. In some embodiments, the centrifugation of step (j) is for 20 minutes. In some embodiments, the centrifugation of step (j) is at 4 C or room temperature. In some embodiments, the fourth solution in step (k) is 100mM Tris-HC1, pH 7.5 or PBS.
[1544] pmEVs obtained by methods provided herein may be further purified by size based column chromatography, by affinity chromatography, and by gradient ultracentrifugation, using methods that may include, but are not limited to, use of a sucrose gradient or Optiprep gradient. Briefly, using a sucrose gradient method, if ammonium sulfate precipitation or ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in 60% sucrose, 30 mM Tris, pH 8Ø If filtration was used to concentrate the filtered supernatant, the concentrate is buffer exchanged into 60%
sucrose, 30 mM Tris, pH 8.0, using an Amicon Ultra column. Samples are applied to a 35-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4 C.
Briefly, using an Optiprep gradient method, if ammonium sulfate precipitation or ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in 35% Optiprep in PBS. In some embodiments, if filtration was used to concentrate the filtered supernatant, the concentrate is diluted using 60%
Optiprep to a final concentration of 35% Optiprep. Samples are applied to a 35-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4 C.
[1545] In some embodiments, to confirm sterility and isolation of the pmEV
preparations, pmEVs are serially diluted onto agar medium used for routine culture of the bacteria being tested, and incubated using routine conditions. Non-sterile preparations are passed through a 0.22 um filter to exclude intact cells. To further increase purity, isolated pmEVs may be DNase or proteinase K treated.
[1546] In some embodiments, the sterility of the pmEV preparations can be confirmed by plating a portion of the pmEVs onto agar medium used for standard culture of the bacteria used in the generation of the pmEVs and incubating using standard conditions.

[1547] In some embodiments select pmEVs are isolated and enriched by chromatography and binding surface moieties on pmEVs. In other embodiments, select pmEVs are isolated and/or enriched by fluorescent cell sorting by methods using affinity reagents, chemical dyes, recombinant proteins or other methods known to one skilled in the art.
[1548] The pmEVs can be analyzed, e.g., as described in Jeppesen, et al.
Cell 177:428 (2019).
[1549] In some embodiments, pmEVs are lyophilized.
[1550] In some embodiments, pmEVs are gamma irradiated (e.g., at 17.5 or kGy).
[1551] In some embodiments, pmEVs are UV irradiated.
[1552] In some embodiments, pmEVs are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).
[1553] In some embodiments, pmEVs are acid treated.
[1554] In some embodiments, pmEVs are oxygen sparged (e.g., at 0.1 vvm for two hours).
[1555] The phase of growth can affect the amount or properties of bacteria. In the methods of pmEV preparation provided herein, pmEVs can be isolated, e.g., from a culture, at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.
Production of Secreted Microbial Extracellular Vesicles (smEVs) [1556] In certain aspects, the smEVs described herein can be prepared using any method known in the art.
[1557] In some embodiments, the smEVs are prepared without an smEV
purification step. For example, in some embodiments, bacteria described herein are killed using a method that leaves the smEVs intact and the resulting bacterial components, including the smEVs, are used in the methods and compositions described herein. In some embodiments, the bacteria are killed using an antibiotic (e.g., using an antibiotic described herein). In some embodiments, the bacteria are killed using UV irradiation. In some embodiments, the bacteria are heat-killed.
[1558] In some embodiments, the smEVs described herein are purified from one or more other bacterial components. Methods for purifying smEVs from bacteria are known in the art. In some embodiments, smEVs are prepared from bacterial cultures using methods described in S. Bin Park, et al. PLoS ONE. 6(3):e17629 (2011) or G. Norheim, et al. PLoS
ONE. 10(9): e0134353 (2015) or Jeppesen, et al. Cell 177:428 (2019), each of which is hereby incorporated by reference in its entirety. In some embodiments, the bacteria are cultured to high optical density and then centrifuged to pellet bacteria (e.g., at 10,000 x g for 30 min at 4 C, at 15,500 x g for 15 min at 4 C). In some embodiments, the culture supernatants are then passed through filters to exclude intact bacterial cells (e.g., a 0.22 [tm filter). In some embodiments, the supernatants are then subjected to tangential flow filtration, during which the supernatant is concentrated, species smaller than 100 kDa are removed, and the media is partially exchanged with PBS. In some embodiments, filtered supernatants are centrifuged to pellet bacterial smEVs (e.g., at 100,000-150,000 x g for 1-3 hours at 4 C, at 200,000 x g for 1-3 hours at 4 C). In some embodiments, the smEVs are further purified by resuspending the resulting smEV pellets (e.g., in PBS), and applying the resuspended smEVs to an Optiprep (iodixanol) gradient or gradient (e.g., a 30-60%
discontinuous gradient, a 0-45% discontinuous gradient), followed by centrifugation (e.g., at 200,000 x g for 4-20 hours at 4 C). smEV bands can be collected, diluted with PBS, and centrifuged to pellet the smEVs (e.g., at 150,000 x g for 3 hours at 4 C, at 200,000 x g for 1 hour at 4 C). The purified smEVs can be stored, for example, at -80 C or -20 C
until use.
In some embodiments, the smEVs are further purified by treatment with DNase and/or proteinase K.
[1559] For example, in some embodiments, cultures of bacteria can be centrifuged at 11,000 x g for 20-40 min at 4 C to pellet bacteria. Culture supernatants may be passed through a 0.22 [tm filter to exclude intact bacterial cells. Filtered supernatants may then be concentrated using methods that may include, but are not limited to, ammonium sulfate precipitation, ultracentrifugation, or filtration. For example, for ammonium sulfate precipitation, 1.5-3 M ammonium sulfate can be added to filtered supernatant slowly, while stirring at 4 C. Precipitations can be incubated at 4 C for 8-48 hours and then centrifuged at 11,000 x g for 20-40 min at 4 C. The resulting pellets contain bacteria smEVs and other debris. Using ultracentrifugation, filtered supernatants can be centrifuged at 100,000-200,000 x g for 1-16 hours at 4 C. The pellet of this centrifugation contains bacteria smEVs and other debris such as large protein complexes. In some embodiments, using a filtration technique, such as through the use of an Amicon Ultra spin filter or by tangential flow filtration, supernatants can be filtered so as to retain species of molecular weight > 50 or 100 kDa.
[1560] Alternatively, smEVs can be obtained from bacteria cultures continuously during growth, or at selected time points during growth, for example, by connecting a bioreactor to an alternating tangential flow (ATF) system (e.g., XCell ATF
from Repligen).
The ATF system retains intact cells (>0.22 um) in the bioreactor, and allows smaller components (e.g., smEVs, free proteins) to pass through a filter for collection. For example, the system may be configured so that the <0.22 um filtrate is then passed through a second filter of 100 kDa, allowing species such as smEVs between 0.22 um and 100 kDa to be collected, and species smaller than 100 kDa to be pumped back into the bioreactor.
Alternatively, the system may be configured to allow for medium in the bioreactor to be replenished and/or modified during growth of the culture. smEVs collected by this method may be further purified and/or concentrated by ultracentrifugation or filtration as described above for filtered supernatants.
[1561] smEVs obtained by methods provided herein may be further purified by size-based column chromatography, by affinity chromatography, by ion-exchange chromatography, and by gradient ultracentrifugation, using methods that may include, but are not limited to, use of a sucrose gradient or Optiprep gradient. Briefly, using a sucrose gradient method, if ammonium sulfate precipitation or ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in 60% sucrose, 30 mM Tris, pH 8Ø If filtration was used to concentrate the filtered supernatant, the concentrate is buffer exchanged into 60% sucrose, 30 mM Tris, pH 8.0, using an Amicon Ultra column.
Samples are applied to a 35-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4 C. Briefly, using an Optiprep gradient method, if ammonium sulfate precipitation or ultracentrifugation were used to concentrate the filtered supernatants, pellets are resuspended in PBS and 3 volumes of 60% Optiprep are added to the sample. In some embodiments, if filtration was used to concentrate the filtered supernatant, the concentrate is diluted using 60% Optiprep to a final concentration of 35%
Optiprep.
Samples are applied to a 0-45% discontinuous Optiprep gradient and centrifuged at 200,000 x g for 3-24 hours at 4 C, e.g., 4-24 hours at 4 C.
[1562] In some embodiments, to confirm sterility and isolation of the smEV
preparations, smEVs are serially diluted onto agar medium used for routine culture of the bacteria being tested, and incubated using routine conditions. Non-sterile preparations are passed through a 0.22 um filter to exclude intact cells. To further increase purity, isolated smEVs may be DNase or proteinase K treated.
[1563] In some embodiments, for preparation of smEVs used for in vivo injections, purified smEVs are processed as described previously (G. Norheim, et al. PLoS
ONE.
10(9): e0134353 (2015)). Briefly, after sucrose gradient centrifugation, bands containing smEVs are resuspended to a final concentration of 50 [tg/mL in a solution containing 3%
sucrose or other solution suitable for in vivo injection known to one skilled in the art. This solution may also contain adjuvant, for example aluminum hydroxide at a concentration of 0-0.5% (w/v). In some embodiments, for preparation of smEVs used for in vivo injections, smEVs in PBS are sterile-filtered to < 0.22 um.
[1564] In certain embodiments, to make samples compatible with further testing (e.g., to remove sucrose prior to TEM imaging or in vitro assays), samples are buffer exchanged into PBS or 30 mM Tris, pH 8.0 using filtration (e.g., Amicon Ultra columns), dialysis, or ultracentrifugation (200,000 x g, > 3 hours, 4 C) and resuspension.
[1565] In some embodiments, the sterility of the smEV preparations can be confirmed by plating a portion of the smEVs onto agar medium used for standard culture of the bacteria used in the generation of the smEVs and incubating using standard conditions.
[1566] In some embodiments, select smEVs are isolated and enriched by chromatography and binding surface moieties on smEVs. In other embodiments, select smEVs are isolated and/or enriched by fluorescent cell sorting by methods using affinity reagents, chemical dyes, recombinant proteins or other methods known to one skilled in the art.
[1567] The smEVs can be analyzed, e.g., as described in Jeppesen, et al.
Cell 177:428 (2019).
[1568] In some embodiments, smEVs are lyophilized.
[1569] In some embodiments, smEVs are gamma irradiated (e.g., at 17.5 or kGy).
[1570] In some embodiments, smEVs are UV irradiated.
[1571] In some embodiments, smEVs are heat inactivated (e.g., at 50 C for two hours or at 90 C for two hours).
[1572] In some embodiments, smEVs s are acid treated.
[1573] In some embodiments, smEVs are oxygen sparged (e.g., at 0.1 vvm for two hours).

[1574] The phase of growth can affect the amount or properties of bacteria and/or smEVs produced by bacteria. For example, in the methods of smEV preparation provided herein, smEVs can be isolated, e.g., from a culture, at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.
[1575] The growth environment (e.g., culture conditions) can affect the amount of smEVs produced by bacteria. For example, the yield of smEVs can be increased by an smEV inducer, as provided in Table 4.
Table 4: Culture Techniques to Increase smEV Production smEV inducement smEV inducer Acts on Temperature Heat stress response RT to 37 C temp change simulates infection 37 to 40 C temp change febrile infection ROS
Plumbagin oxidative stress response Cumene hydroperoxide oxidative stress response Hydrogen Peroxide oxidative stress response Antibiotics Ciprofloxacin bacterial SOS response Gentamycin protein synthesis Polymyxin B outer membrane D-cylcloserine cell wall Osmolyte NaCl osmotic stress Metal Ion Stress Iron Chelation iron levels EDTA removes divalent cations Low Hemin iron levels Media additives or removal Lactate growth Amino acid deprivation stress Hexadecane stress Glucose growth Sodium bicarbonate ToxT induction PQS vesiculator (from bacteria) membmne anchoring Diamines+ DFMO (negativicutes only) High nutrients enhanced growth Low nutrients Other mechanisms Oxygen oxygen stress in anaerobe No Cysteine oxygen stress in anaerobe Inducing biofilm or floculation Diauxic Growth Phage Urea [1576] In the methods of smEVs preparation provided herein, the method can optionally include exposing a culture of bacteria to an smEV inducer prior to isolating smEVs from the bacterial culture. The culture of bacteria can be exposed to an smEV
inducer at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.
Solid Dosage Form Compositions [1577] In certain embodiments, provided herein are solid dosage forms comprising a pharmaceutical agent that contains bacteria and/or mEVs (such as smEVs and/or pmEVs).
In some embodiments, the pharmaceutical agent can optionally contain one or more additional components, such as a cryoprotectant. The pharmaceutical agent can be lyophilized (e.g., resulting in a powder). The pharmaceutical agent can be combined with one or more excipients (e.g., pharmaceutically acceptable excipients) in the solid dosage form. In some embodiments, the pharmaceutical agent can be (or be present in) a medicinal product, medical food, a food product, or a dietary supplement.
[1578] In certain embodiments, provided herein are solid dosage forms comprising a pharmaceutical agent that contains bacteria. The bacteria can be live bacteria (e.g., powder or biomass thereof); non-live (dead) bacteria (e.g., powder or biomass thereof); non replicating bacteria (e.g., powder or biomass thereof); gamma irradiated bacteria (e.g., powder or biomass thereof); and/or lyophilized bacteria (e.g., powder or biomass thereof).
[1579] In certain embodiments, provided herein are solid dosage forms comprising a pharmaceutical agent that contains mEVs. The mEVs can be from culture media (e.g., culture supernatant). The mEVs can be from live bacteria (e.g., powder or biomass thereof);
the mEVs can be from non-live (dead) bacteria (e.g., powder or biomass thereof); the mEVs can be from non replicating bacteria (e.g., powder or biomass thereof); the mEVs can be from gamma irradiated bacteria (e.g., powder or biomass thereof); and/or the mEVs can be from lyophilized bacteria (e.g., powder or biomass thereof).
[1580] In some embodiments, the pharmaceutical agent comprises mEVs substantially or entirely free of bacteria (e.g., whole bacteria) (e.g., live bacteria, dead (e.g., killed) bacteria, non-replicating bacteria, attenuated bacteria. In some embodiments, the pharmaceutical agents comprise both mEVs and bacteria (e.g., whole bacteria) (e.g., live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the pharmaceutical agents comprise bacteria and/or mEVs from one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) of the bacteria strains or species listed herein. In some embodiments, the pharmaceutical agents comprise bacteria and/or mEVs from one of the bacteria strains or species listed herein. In some embodiments, the pharmaceutical agents comprise lyophilized bacteria and/or mEVs. In some embodiments, the pharmaceutical agent comprises gamma irradiated bacteria and/or mEVs. The mEVs (such as smEVs and/or pmEVs) can be gamma irradiated after the mEVs are isolated (e.g., prepared).
[1581] In some embodiments, to quantify the numbers of mEVs (such as smEVs and/or pmEVs) and/or bacteria present in a sample, electron microscopy (e.g., EM of ultrathin frozen sections) can be used to visualize the mEVs (such as smEVs and/or pmEVs) and/or bacteria and count their relative numbers. Alternatively, nanoparticle tracking analysis (NTA), Coulter counting, or dynamic light scattering (DLS) or a combination of these techniques can be used. NTA and the Coulter counter count particles and show their sizes. DLS gives the size distribution of particles, but not the concentration.
Bacteria frequently have diameters of 1-2 um (microns). The full range is 0.2-20 um.
Combined results from Coulter counting and NTA can reveal the numbers of bacteria and/or mEVs (such as smEVs and/or pmEVs) in a given sample. Coulter counting reveals the numbers of particles with diameters of 0.7-10 um. For most bacterial and/or mEV (such as smEV and/or pmEV) samples, the Coulter counter alone can reveal the number of bacteria and/or mEVs (such as smEVs and/or pmEVs) in a sample. pmEVs are 20-600 nm in diameter. For NTA, a Nanosight instrument can be obtained from Malvern Pananlytical.
For example, the NS300 can visualize and measure particles in suspension in the size range 10-2000nm. NTA allows for counting of the numbers of particles that are, for example, 50-1000 nm in diameter. DLS reveals the distribution of particles of different diameters within an approximate range of 1 nm ¨ 3 um.

[1582] mEVs can be characterized by analytical methods known in the art (e.g., Jeppesen, et al. Cell 177:428 (2019)).
[1583] In some embodiments, the bacteria and/or mEVs may be quantified based on particle count. For example, particle count of a bacteria and/or mEV
preparation can be measured using NTA.
[1584] In some embodiments, the bacteria and/or mEVs may be quantified based on the amount of protein, lipid, or carbohydrate. For example, total protein content of a bacteria and/or preparation can be measured using the Bradford assay or BCA.
[1585] In some embodiments, mEVs are isolated away from one or more other bacterial components of the source bacteria or bacterial culture. In some embodiments, bacteria are isolated away from one or more other bacterial components of the source bacterial culture. In some embodiments, the pharmaceutical agent further comprises other bacterial components.
[1586] In certain embodiments, the mEV preparation obtained from the source bacteria may be fractionated into subpopulations based on the physical properties (e.g., sized, density, protein content, binding affinity) of the subpopulations. One or more of the mEV subpopulations can then be incorporated into the pharmaceutical agents of the invention.
[1587] In certain aspects, provided herein are solid dosage forms comprising pharmaceutical agents that comprise bacteria and/or mEVs (such as smEVs and/or pmEVs) useful for the treatment and/or prevention of disease (e.g., a cancer, an autoimmune disease, an inflammatory disease, or a metabolic disease), as well as methods of making and/or identifying such bacteria and/or mEVs, and methods of using pharmaceutical agents and solid dosage forms thereof (e.g., for the treatment of a cancer, an autoimmune disease, an inflammatory disease, or a metabolic disease, either alone or in combination with other therapeutics). In some embodiments, the pharmaceutical agents comprise both mEVs (such as smEVs and/or pmEVs) and bacteria (e.g., whole bacteria) (e.g., live bacteria, dead (e.g., killed) bacteria, non-replicating bacteria, attenuated bacteria). In some embodiments, the pharmaceutical agents comprise bacteria in the absence of mEVs (such as smEVs and/or pmEVs). In some embodiments, the pharmaceutical agents comprise mEVs (such as smEVs and/or pmEVs) in the absence of bacteria. In some embodiments, the pharmaceutical agents comprise mEVs (such as smEVs and/or pmEVs) and/or bacteria from one or more of the bacteria strains or species listed herein. In some embodiments, the pharmaceutical agents comprise mEVs (such as smEVs and/or pmEVs) and/or bacteria from one of the bacteria strains or species listed herein.
[1588] In certain aspects, provided are pharmaceutical agents for administration to a subject (e.g., human subject). In some embodiments, the pharmaceutical agents are combined with additional active and/or inactive materials in order to produce a final product, which may be in single dosage unit or in a multi-dose format. In some embodiments, the pharmaceutical agent is combined with an adjuvant such as an immuno-adjuvant (e.g., a STING agonist, a TLR agonist, or a NOD agonist).
[1589] In some embodiments, the solid dosage form comprises at least one carbohydrate.
[1590] In some embodiments, the solid dosage form comprises at least one lipid. In some embodiments, the lipid comprises at least one fatty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), margaric acid (17:0), heptadecenoic acid (17:1), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20:1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosenoic acid (22:1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and tetracosanoic acid (24:0).
[1591] In some embodiments, the solid dosage form comprises at least one supplemental mineral or mineral source. Examples of minerals include, without limitation:
chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the foregoing minerals include soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals, and reduced minerals, and combinations thereof.
[1592] In some embodiments, the solid dosage form comprises at least one vitamin.
The at least one vitamin can be fat-soluble or water-soluble vitamins.
Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin. Suitable forms of any of the foregoing are salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of the vitamin.

[1593] In some embodiments, the solid dosage form comprises an excipient.
Non-limiting examples of suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, and a coloring agent.
[1594] Suitable excipients that can be included in the solid dosage form can be one or more pharmaceutically acceptable excipients known in the art. For example, see Rowe, Sheskey, and Quinn, eds., Handbook of Pharmaceutical Excipients, sixth ed.;
2009;
Pharmaceutical Press and American Pharmacists Association.
Solid Dosage Forms [1595] The solid dosage form described herein can be, e.g., a tablet or a minitablet.
Further, a plurality of minitablets can be in (e.g., loaded into) a capsule.
[1596] In certain embodiments, the solid dosage form comprises a capsule.
In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
In some embodiments, the capsule is a size 0 capsule. As used herein, the size of the capsule refers to the size of the tablet prior to application of an enteric coating. In some embodiments, the capsule is banded after loading (and prior to enterically coating the capsule). In some embodiments, the capsule is banded with an HPMC-based banding solution.
[1597] In some embodiments, the solid dosage form comprises a tablet (>
4mm) (e.g., 5mm-17mm). For example, the tablet is a 5mm, 6mm, 7mm, 8mm, 9mm, lOmm, llmm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, or 18mm tablet. The size refers to the diameter of the tablet, as is known in the art. As used herein, the size of the tablet refers to the size of the tablet prior to application of an enteric coating.
[1598] In some embodiments, the solid dosage form comprises a minitablet.
The minitablet can be in the size range of lmm-4 mm range. E.g., the minitablet can be a lmm minitablet, 1.5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet. The size refers to the diameter of the minitablet, as is known in the art. As used herein, the size of the minitablet refers to the size of the minitablet prior to application of an enteric coating.
[1599] The minitablets can be in a capsule. The capsule can be a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. The capsule that contains the minitablets can comprise HPMC (hydroxyl propyl methyl cellulose) or gelatin. The minitablets can be inside a capsule: the number of minitablets inside a capsule will depend on the size of the capsule and the size of the minitablets. As an example, a size 0 capsule can contain 31-35 (an average of 33) minitablets that are 3mm minitablets. In some embodiments, the capsule is banded after loading. In some embodiments, the capsule is banded with an HPMC-based banding solution.
Coating:
[1600] The solid dosage form (e.g., capsule, tablet or minitablet) described herein can be enterically coated, e.g., with one enteric coating layer or with two layers of enteric coating, e.g., an inner enteric coating and an outer enteric coating. The inner enteric coating and outer enteric coating are not identical (e.g., the inner enteric coating and outer enteric coating do not contain the same components in the same amounts). The enteric coating allows for release of the pharmaceutical agent, e.g., in the small intestine.
[1601] Release of the pharmaceutical agent in the small intestine allows the pharmaceutical agent to target and affect cells (e.g., epithelial cells and/or immune cells) located at these specific locations, e.g., which can cause a local effect in the gastrointestinal tract and/or cause a systemic effect (e.g., an effect outside of the gastrointestinal tract).
[1602] EUDRAGIT is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.
[1603] Examples of other materials that can be used in the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) include cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (esters of aleurtic acid), plastics, plant fibers, zein, Aqua-Zeing (an aqueous zein formulation containing no alcohol), amylose starch, starch derivatives, dextrins, methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymers, and/or sodium alginate.
[1604] The enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) can include a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

[1605] The one enteric coating can include methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).
[1606] The one enteric coating can include a Eudragit coplymer, e.g., a Eudragit L
(e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS 30 D).
[1607] Other examples of materials that can be used in the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) include those described in, e.g., U.S. 6312728; U.S. 6623759; U.S. 4775536; U.S.
5047258; U.S.
5292522; U.S. 6555124; U.S. 6638534; U.S. 2006/0210631; U.S. 2008/200482; U.S.

2005/0271778; U.S. 2004/0028737; WO 2005/044240.
[1608] See also, e.g., U.S. 9233074, which provides pH dependent, enteric polymers that can be used with the solid dosage forms provided herein, including methacrylic acid copolymers, polyvinylacetate phthalate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate and cellulose acetate phthalate;
suitable methacrylic acid copolymers include: poly(methacrylic acid, methyl methacrylate) 1:1 sold, for example, under the Eudragit L100 trade name; poly(methacrylic acid, ethyl acrylate) 1:1 sold, for example, under the Eudragit L100-55 trade name;
partially-neutralized poly(methacrylic acid, ethyl acrylate) 1:1 sold, for example, under the Kollicoat MAE-10OP trade name; and poly(methacrylic acid, methyl methacrylate) 1:2 sold, for example, under the Eudragit S100 trade name.
[1609] In some embodiments, the solid dosage form comprises a sub-coat, e.g., under the enteric coating (e.g., one enteric coating). The sub-coat can be used, e.g., to visually mask the appearance of the pharmaceutical agent.
Dose [1610] The dose of the pharmaceutical agent (e.g., for human subjects) is the dose per capsule or tablet or per total number of minitablets used in a capsule.
[1611] In embodiments where dose is determined by total cell count, total cell count can be determined by Coulter counter.
[1612] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 107 to about 2 x 1012 (e.g., about 3 x 1010 or about 1.5 x 1011 or about 1.5 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 1010 to about 2 x 1012 (e.g., about 1.6 x 1011 or about 8 x 1011 or about 9.6 x 1011 about 12.8 x 1011 or about 1.6 x 1012) cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.
[1613] In some embodiments, the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 109, about 3 x 109, about 5 x 109, about 1.5 x 1010, about 3 x 1010, about 5 x 1010, about 1.5 x 1011, about 1.5 x 1012, or about 2 x 1012 cells, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.
[1614] In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 105 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises mEVs and the dose of mEVs is about 1 x 1010 to about 7 x 1013 particles (e.g., wherein particle count is determined by NTA
(nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.
[1615] In some embodiments, wherein the pharmaceutical agent comprises mEVs, the dose of mEVs is about 2x106 to about 2x1016 particles (e.g., wherein particle count is determined by NTA (nanoparticle tracking analysis)), wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.
[1616] The solid dosage form allows higher efficacy if used at the same dose as in powder form; and/or allows a reduced dose (e.g., 1/10 lower dose) for similar efficacy as when the pharmaceutical agent is used in powder form.
[1617] In some embodiments, wherein the pharmaceutical agent comprises bacteria, the dose can be approximately 1/10 dose for similar efficacy as when the pharmaceutical agent is used in powder form and the dose can be about 3 x 109 or about 1.5 x 1010 cells per dose.
[1618] The solid dosage form can allow higher efficacy if used at the same dose of the pharmaceutical agent as in a powder formulation.

[1619] In some embodiments, the pharmaceutical agent dose can be a milligram (mg) dose determined by weight the pharmaceutical agent. The dose of the pharmaceutical agent is per capsule or tablet or per total number of minitablets, e.g., in a capsule.
[1620] For example, to administer a lx dose of the pharmaceutical agent of about 400 mg, about 200 mg of the pharmaceutical agent is present per capsule and two capsules are administered, resulting in a dose of about 400 mg. The two capsules can be administered, for example, lx or 2x daily.
[1621] As another example, to obtain similar efficacy as a powder form of the pharmaceutical agent, the dose of pharmaceutical agent can be reduced by 1/10 when prepared as a solid dosage form described herein (e.g., by enterically coating a tablet or minitablet containing the pharmaceutical agent.
[1622] For example, for a minitablet: about 0.1 to about 3.5 mg (0.1, 0.35, 1.0, 3.5 mg) of the pharmaceutical agent can be contained per minitablet. The minitablets can be inside a capsule: the number of minitablets inside a capsule will depend on the size of the capsule and the size of the minitablets. For example, an average of 33 (range of 31-35) 3mm minitablets fit inside a size 0 capsule. As an example, 0.1- 3.5 mg of the pharmaceutical agent per minitablet, the dose range will be 3.3 mg- 115.5 mg (for 33 minitablets in size 0 capsule) per capsule (3.1 mg- 108.5 mg for 31 minitablets in size 0 capsule) (3.5 mg- 122.5 mg for 35 minitablets in size 0 capsule). Multiple capsules and/or larger capsule(s) can be administered to increase the administered dose and/or can be administered one or more times per day to increase the administered dose.
[1623] In some embodiments, the dose can be about 3 mg to about 125 mg of the pharmaceutical agent, per capsule or tablet or per total number of minitablets, e.g., in a capsule.
[1624] In some embodiments, the dose can be about 35 mg to about 1200 mg (e.g., about 35 mg, about 125 mg, about 350 mg, or about 1200 mg) of the pharmaceutical agent.
[1625] In some embodiments, the dose of the pharmaceutical agent can be about 30 mg to about 3500 mg (about 25, about 50, about 75, about 100, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 750, about 1000, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg).
[1626] A human dose can be calculated appropriately based on allometric scaling of a dose administered to a model organism (e.g., mouse).

[1627] In some embodiments, one or two tablets capsules can be administered one or two times a day.
[1628] The pharmaceutical agent contains the bacteria and/or mEVs and can also contain one or more additional components, such as cryoprotectants, stabilizers, etc.
[1629] In some embodiments, the mg (by weight) dose of the pharmaceutical agent is, e.g., about 1 mg to about 500 mg per capsule, or per tablet, or per total number of minitablets, e.g., used in a capsule.
Methods of Use [1630] The solid dosage forms described herein allow, e.g., for oral administration of a pharmaceutical agent contained therein.
[1631] The solid dosage forms described herein can provide an increase in therapeutic efficacy and/or physiological effect as compared to other dosage forms (e.g., non-enterically coated dosage forms (e.g., non-minitablet non-enterically coated dosage forms, or non-tablet non-enterically coated dosage forms) or a suspension of biomass or powder).
[1632] The solid dosage forms described herein can provide release in the small intestine of the pharmaceutical agent contained in the solid dosage form.
[1633] The solid dosage forms described herein can provide release of the pharmaceutical agent in the small intestine, e.g., to deliver the pharmaceutical agent that can act on immune cells and/or epithelial cells in the small intestine, e.g., to cause a systemic effect (e.g., an effect outside of the gastrointestinal tract) and/or a local effect in the gastrointestinal tract.
[1634] The solid dosage forms described herein can provide increased efficacy and/or physiological effect (as measured by a systemic effect (e.g., outside of the gastrointestinal tract) of the pharmaceutical agent, e.g., in ear thickness in a DTH model for inflammation; tumor size in cancer model), e.g., as compared to oral gavage of the same dose of pharmaceutical agent.
[1635] The solid dosage forms described herein can be used in the treatment and/or prevention of a cancer, inflammation, autoimmunity, or a metabolic condition.
[1636] Methods of using a solid dosage form (e.g., for oral administration) (e.g., for pharmaceutical use) comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated are described herein.
[1637] The methods and administered solid dosage forms described herein allow, e.g., for oral administration of a pharmaceutical agent contained therein. The solid dosage form can be administered to a subject is a fed or fasting state. The solid dosage form can be administered, e.g., on an empty stomach (e.g., one hour before eating or two hours after eating). The solid dosage form can be administered one hour before eating. The solid dosage form can be administered two hours after eating.
[1638] The methods and administered solid dosage forms described herein can provide an increase in therapeutic efficacy and/or physiological effect as compared to other dosage forms (e.g., non-enterically coated dosage forms (e.g., non-minitablet non-enterically coated dosage forms, or non-tablet non-enterically coated dosage forms) or a suspension of biomass or powder).
[1639] The methods and administered solid dosage forms described herein can provide release in the small intestine of the pharmaceutical agent contained in the solid dosage form.
[1640] The methods and administered solid dosage forms described herein can provide release of the pharmaceutical agent in the small intestine, e.g., to deliver the pharmaceutical agent that can act on immune cells and/or epithelial cells in the small intestine, e.g., to cause a systemic effect (e.g., an effect outside of the gastrointestinal tract) and/or a local effect in the gastrointestinal tract.
[1641] The methods and administered solid dosage forms described herein can provide increased efficacy and/or physiological effect (as measured by a systemic effect (e.g., outside of the gastrointestinal tract) of the pharmaceutical agent, e.g., in ear thickness in a DTH model for inflammation; tumor size in cancer model), e.g., as compared to oral gavage of the same dose of pharmaceutical agent.
[1642] The methods and administered solid dosage forms described herein can be used in the treatment and/or prevention of a cancer, inflammation, autoimmunity, dysbiosis, or a metabolic condition.
[1643] A solid dosage form for use in the treatment and/or prevention of a cancer, inflammation, autoimmunity, dysbiosis, or a metabolic condition is provided herein.

[1644] Use of a solid dosage form for the preparation of a medicament for the treatment and/or prevention of a cancer, inflammation, autoimmunity, dysbiosis, or a metabolic condition is provided herein.
Method of Making Solid Dosage Forms [1645] The disclosure also provides methods of making a solid dosage form (e.g., for oral administration) (e.g., for pharmaceutical use) that comprises a pharmaceutical agent. The pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs). The pharmaceutical agent can also contain one or more additional components (e.g., a cryoprotectant). The solid dosage form is enterically coated.
[1646] A method of making the solid dosage form can include:
[1647] Loading the pharmaceutical agent into a capsule; and [1648] Coating the capsule with one or two layers of enteric coating (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing an enterically coated capsule, and thereby preparing the solid dosage form;
[1649] Optionally combining the pharmaceutical agent with a pharmaceutically acceptable excipient prior to loading into the capsule; and/or [1650] Optionally banding the capsule after loading the capsule (e.g., optionally banding the capsule after loading the capsule and prior to enterically coating the capsule).
[1651] A method of making the solid dosage form can include:
[1652] Compressing a pharmaceutical agent described herein into a minitablet; and [1653] Coating the minitablet with one or two layers of enteric coating (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing an enterically coated minitablet;
[1654] Optionally filling a capsule with a plurality of enterically coated minitablets, thereby preparing the solid dosage form.
[1655] A method of making the solid dosage form can include:
[1656] Compressing a pharmaceutical agent described herein into a tablet;
and [1657] Coating the tablet with one or two layers of enteric coating (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing enterically coated tablet, and thereby preparing the solid dosage form.

[1658] A method of making the solid dosage form can include a method for preparing an enterically coated capsule comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
[1659] a) loading the pharmaceutical agent into a capsule; and [1660] b) enterically coating the capsule (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing the enterically coated capsule (thereby preparing the solid dosage form).
[1661] A method of making the solid dosage form can include a method for preparing an enterically coated capsule comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
[1662] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
[1663] b) loading the pharmaceutical agent and pharmaceutically acceptable excipient into a capsule; and [1664] c) enterically coating the capsule (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing the enterically coated capsule (thereby preparing the solid dosage form).
[1665] A method of making the solid dosage form can include a method for preparing an enterically coated capsule comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
[1666] a) loading the pharmaceutical agent into a capsule;
[1667] b) banding the capsule; and [1668] c) enterically coating the capsule (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing the enterically coated capsule (thereby preparing the solid dosage form).
[1669] A method of making the solid dosage form can include a method for preparing an enterically coated capsule comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:

[1670] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
[1671] b) loading the pharmaceutical agent and pharmaceutically acceptable excipient into a capsule;
[1672] c) banding the capsule; and [1673] d) enterically coating the capsule (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing the enterically coated capsule (thereby preparing the solid dosage form).
[1674] A method of making the solid dosage form can include a method for preparing an enterically coated tablet comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
[1675] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
[1676] b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a tablet; and [1677] c) enterically coating the tablet (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing the enterically coated tablet (thereby preparing the solid dosage form).
[1678] A method of making the solid dosage form can include a method for preparing an enterically coated minitablet comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
[1679] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
[1680] b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a minitablet; and [1681] c) enterically coating the minitablet (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), thereby preparing the enterically coated minitablet (thereby preparing the solid dosage form).
Optionally, the minitablet is loaded into a capsule.
[1682] A method of making the solid dosage form can include a method for preparing a capsule comprising enterically coated minitablets comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
[1683] a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
[1684] b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a minitablet;
[1685] c) enterically coating the minitablet (e.g., with an enteric coating or inner enteric coating and outer enteric coating as described herein), and [1686] d) loading the capsule with enterically coated minitablets, [1687] thereby preparing the capsule (thereby preparing the solid dosage form).
Additional Aspects of the Solid Dosage Forms [1688] The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated, can provide a therapeutically effective amount of the pharmaceutical agent to a subject, e.g., a human.
[1689] The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated, can provide a non-natural amount of the therapeutically effective components (e.g., present in the pharmaceutical agent) to a subject, e.g., a human.
[1690] The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated, can provide an unnatural quantity of the therapeutically effective components (e.g., present in the pharmaceutical agent) to a subject, e.g., a human.
[1691] The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the therapeutic agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated, can bring about one or more changes to a subject, e.g., human, e.g., to treat or prevent a disease or a health disorder.
[1692] The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated, has potential for significant utility, e.g., to affect a subject, e.g., a human, e.g., to treat or prevent a disease or a health disorder.
Other Content of Solid Dosage Forms [1693] The solid dosage forms described herein (e.g., enterically coated tablets or minitablets) can be used to deliver an additional pharmaceutical agent (e.g., in place of, or in addition to, a pharmaceutical agent that comprises bacteria and/or mEVs (e.g., as defined herein)), such as a small molecule, vitamin or mineral supplement, or dietary supplement, to the small intestine.
[1694] Additional pharmaceutical agents that contain a small molecule that can be prepared in a solid dosage form described herein include one or more of the following small molecules: analgesics, anti-inflammatories, anaesthetics, anticonvulsants, antidiabetic agents, antihistamines, anti-infectives, antineoplastics, antiparkinsonian agents, antirheumatic agents, appetite stimulants, appetite suppressants, blood modifiers, bone metabolism modifiers, cardiovascular agents, central nervous system depressants, central nervous system stimulants, decongestants, dopamine receptor agonists, electrolytes, gastrointestinal agents, immunomodulators, muscle relaxants, narcotics, parasympathomimetics, sympathomimetics, sedatives, and hypnotics; pirenzepine, misoprostol, ursodeoxycholic acid, Alosetron, Cilansetron, Mosapride, Prucalopride, Tegaserod, Metoclopramide, Bromopride, Clebopride, Domperidone, Alizapride, Cinitapride, Cisapride, Codeine, Morphine, loperamide, diphenoxylate, methylnaltrexone bromide, Valerian, and mannitol; Antispasmodics selected from the group consisting of atropine sulphate, dicycloverine hydrochloride, hyoscine butylbromine, propantheline bromide, alverine citrate, and mebeverine hydrochloride; Motility stimulants selected from the group consisting of metoclorpramide and domperidone; H2-Receptor antagonists selected from the group consisting of Cimetidine, famotidinenizatidine, and ranitidine;
Antimuscarinics; Chelates selected from the group consisting of Tripotassium dicitratbismuthate and sucralfate; Prostaglandin analogues; Aminosalicylates selected from the group consisting of balsazide sodium, mesalazine, olsalazine, and sulphasalazine;
Corticosteroids selected from the group consisting of beclometasone dipropionate, budenoside, hydrocortisone, and prednisolone; Affecting immune response selected from the group consisting of ciclosporin, mercaptopurine, methotrexate, adalimumab, and infliximab; Stimulant Laxatives selected from the group consisting of bisacodyl, dantron, docusate, and sodium picosulfate; Drugs affecting biliary composition and flow; Bile acids sequestrants selected from the group consisting of colestyramine, Oxyphencyclimine, Camylofin, Mebeverine, Trimebutine, Rociverine, Dicycloverine, Dihexyverine, Difemerine, Piperidolate, Benzilone, Mepenzolate, Pipenzolate, Glycopyrronium, Oxyphenonium, Penthienate, Methantheline, Propantheline, Otilonium bromide, Tridihexethyl, Isopropamide, Hexocyclium, Poldine, Bevonium, Diphemanil, Tiemonium iodide, Prifinium bromide, Timepidium bromide, Fenpiverinium, Papaverine, Drotaverine, Moxaverine, 5-HT3 antagonists, 5-HT4 agonists, Fenpiprane, Diisopromine, Chlorbenzoxamine, Pinaverium, Fenoverine, Idanpramine, Proxazole, Alverine, Trepibutone, Isometheptene, Caroverine, Phloroglucinol, Silicones, Trimethyldiphenylpropylamine, Atropine, Hyoscyamine, Scopolamine, Butylscopolamine, Methylscopolamine, Methylatropine, Fentonium, Cimetropium bromide, and primarily dopamine antagonists; Proton pump inhibitors selected from the group consisting of Omeprazole, lansoprazole, pantoprazole, esomeprazole, and rabeprazole sodium;
Opioids and opioid receptor antagonists; Analgesics selected from the group consisting of Acetaminophen, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamate, Mefenamic Acid, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Sulindac, Tolmetin, Celecoxib, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphone, Pentazocine, Propoxyphene, and Tramadol; Sleep drugs selected from the group consisting of Nitrazepam, Flurazepam, Loprazolam, Lormetazepam, Temazepam, Zaleplon, Zolpidem, Zopiclone, Chloral Hydrate, Triclofos, Clomethiazole, Quazepam, triazolam, Estazolam, Clonazepam, Alprazolam, Eszopiclone, Rozerem, Trazodone, Amitriptyline, Doxepin, Benzodiazepine drugs, melatonin, diphenhydramine, and herbal remedies; Cardiac glycosides selected from the group consisting of Digoxin and digitoxin;
Phosphodiesterase inhibitors selected from the group consisting of enoximone and milrinone;
Thiazides and related diuretics selected from the group consisting of bendroflumethiazide, chlortalidone, cyclopenthiazide, inapamide, metolazone, and xipamide; Diuretics selected from the group consisting of furosemide, bumetanide, and torasemide; Potassium sparing diuretics and aldosterone antagonists selected from the group consisting of amiloride hydrochloride, triamterene, weplerenone, and spironolactone; Osmotic diuretics; Drugs for arrhythmias selected from the group consisting of adenosine, amiodarone hydrochloride, disopyramide, flecainide acetate, propafenone hydrochloride, and lidocaine hydrochloride;
Beta adrenoreceptor blocking drugs selected from the group consisting of propranolol, atenolol, acebutolol, bisoprolol fumarate, carvedilol, celiprolol, esmolol, lebatolol, metoprolol tartrate, nadolol, nebivolol, oxprenolol, pindolol, solatol, and timolol;
Hypertension drugs selected from the group consisting of ambrisentan, bosentan, diazoxide, hydralazine, iloprost, minoxidil, sildenafil, sitaxentan, sodium nitroprusside, clonidine, methyldopa, moxonidine, guanethidine monosulphate, doxazosin, indoramin, prazosin, terazosin, phenoxybenzamine, and phentolamine mesilate; Drugs affecting the renin-angiotensin system selected from the group consisting of Captropril, Cilazapril, Enalapril Maleate, Fosinopril, Imidapril, Lisinopril, Moexipril, Perindopril Erbumine, Quinapril, Ramipril, Trandolapril, Candesartan Cilexetil, Eprosartan, Irbesartan, Losartan, Olmesartan Medoxomil, Telmisartan, Valsartan, and Aliskiren; Nitrates, calcium channel Blockers, and antianginal drugs selected from the group consisting of Glyceryl trinitrate, Isosorbide Dinitrate, Isosorbide Mononitrate, Amlodipine, Diltiazem, Felodipine, Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nifedipine, Nimodipine, Verapamil, Ivabradine, Nicorandil, and Ranolazine; Peripheral vasodilators and related drugs selected from the group consisting of Cilostazol, Inositol Nicotinate, Moxisylyte, Naftidrofuryl Oxalate, and Pentoxifylline; Sympathomimetics selected from the group consisting of Dopamine, Dopexamine, Ephedrine, Metaraminol, Noradrenaline Acid Tartrate, Norephidrine Bitartrate, and Phenylephidrine; Anticoagulants and protamine selected from the group consisting of Heparin, Bemiparin, Dalteparin, Enoxaparin, Tinzaparin, Danaparoid, Bivalirudin, Lepirudin, Epoprostenol, Fondaprinux, Warfarin, Acenocoumarol, Phenindione, Dabigatran Etexilate, Rivaroxaban, and Protamine Sulphate;
Antiplatelet drugs selected from the group consisting of Abciximab, Asprin, Clopidogrel, Dipyridamole, Eptifibatide, Prasugrel, and Tirofiban; Fibrinolytic and antifibrinolytic drugs selected from the group consisting of Alteplase, Reteplase, Streptokinase, Tenecteplase, Urokinase, Etamsylate, and Tranexamic Acid; Lipid regulating drugs selected from the group consisting of Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Simvastatin, Colesevam, Colestyramine, Colestipol, Ezetimibe, Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozyl, Acipmox, Nictotinic Acid, Omega three fatty acid compounds, Ethanolamine Oleate, and Sodium Tetradecyl Suphate; CNS Drugs selected from the group consisting of Benperidol, Chlorpromazine, Flupentixol, Haloperidol, Levomepromazine, Pericyazine, Perphenazine, Pimozide, Prochlorperazine, Promazine, Sulpiride, Trifluoperazine, Zuclopenthixol, Amisulpride, Aripiprazole, Clozapine, Olanzapine, Paliperidone, Quetiapine, Riperidone, Sertindole, Zotepine, Flupentixol, Fluphenazine, Olanzapine Embonate, Pipotiazine Palmitate, Risperidone, Zuclopenthixol Decanoate, Carbamazepine, Valproate, Valproic acid, Lithium Carbonate, Lithium Citrate, Amitriptyline, Clomipramine, Dosulepin, Imipramine, Lofepramine, Nortriptyline, Trimipramine, mianserin, Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moclobemide, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Agomelatine, Duloxetine, Flupentixol, Mirtazapine, Reboxetine, Trytophan, Venflaxine, Atomoxetine, Dexametamine, Methylphenidate, Modafinil, Eslicarbazepine, Ocarbazepene, Ethosuximide, Gabapentin, Pregabalin, Lacosamide, Lamotrigine, Levetiracetam, Phenobarbital, Primidone, Phenytoin, Rufinamide, Tiagabine, Topiramate, Vigabatrin, Zonisamide, ropinirole, Rotigotine, Co-Beneldopa, Levodopa, Co-Careldopa, Rasagiline, Selegiline, Entacapone, Tolcapone, Amantidine, Orphenadrine, Procyclidine, Trihexyphenidyl, Haloperidol, Piracetam, Riluzole, Tetrabenazine, Acamprosate, Disulfiram, Bupropion, Vareniciline, Buprenorphine, Lofexidine, Donepezil, Galantamine, Memantine, and Rivastigimine; Anti-Infectives selected from the group consisting of Benzylpenicillin, Phenoxymethylpenicillin, Flucloxacillin, Temocillin, Amoxicillin, Ampicillin, Co-Amoxiclav, Co-Fluampicil, Piperacillin, Ticarcillin, Pivmecillinam, Cephalosporins, Cefaclor, Cefadroxil, Cefalexin, Cefixime, Cefotaxime, Cefradine, Ceftazidime, Cefuroxime, Ertapenem, Imipenem, Meropenem, Aztreonam, Tetracycline, Demeclocycline, Doxocycline, Lymecycline, Minocycline, Oxytetracycline, Tigecycline, Gentamicin, Amikacin, Neomycin, Tobramycin, Erythromycin, Azithromycin, Clarithromycin, Telithromycin, Clindamycin, Chloramphenicol, Fusidic Acid, Vancomycin, Teicoplanin, Daptomycin, Linezolid, Quinupristin, Colistin, Co-Trimoxazole, Sulpadiazine, Trimethoprim, Capreomycin, Cycloserine, Ethambutol, Isoniazid, Pyrazinamide, Rifabutin, Rifampicin, Streptomycin, Dapsone, Clofazimine, Metronidazole, Tinidazole, Ciproflaxacin, Levoflaxacin, Moxifloxacin, Nalidixic Acid, Norflaxine, Orflaxacin, Nitrofurantoin, Methenamine Hippurate, Amphotericin, Anidulafungin, Caspofungin, Fluconazole, Flucytosine, Griseofluvin, Itraconzole, Ketoconazole, Micafungin, Nystatin, Posaconazole, Terbinafine, Voriconazole, Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir Disoproxil, Zidovudine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinair, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Efavirenz, Etravirine, Nevarapine, Enfuvirtide, Maraviroc, Raltegravir, Aciclovir, Famciclovir, Inosine Pranobex, Valaciclovir, Cidofovir, Gangciclovir, Foscarnet, Valgangciclovir, Adefovir Dipivoxil, Entecavir, Telbivudine, Amantadine, Oseltamivir, Zanamivir, Palivizumab, Ribavirin, Artemether, Chloroquine, Mefloquine, Primaquine, Proguanil, Pyrimethamine, Quinine, Doxycyclin, Diloxanide Furoate, Metronidaziole, Tinidazole, Mepacrine, Sodium Stibogluconate, Atovaquone, Pentamidine Isetionate, Mebendazole, and Piperazine; and other drugs selected from the group consisting of Benztropine, procyclidine, biperiden, Amantadine, Bromocriptine, Pergolide, Entacapone, Tolcapone, Selegeline, Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioglitazone, montelukast, Zoledromic Acid, valsartan, latanoprost, Irbesartan, Clopidogrel, Atomoxetine, Dexamfetamine, Methylphenidate, Modafinil, Bleomycin, Dactinomycin, Daunorubicin, Idarubicin, Mitomycin, Mitoxantrone, Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, Raltitrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Ciclosporine, Sirolimus, Tacrolimus, Interferon Alpha, and Interferon Beta.
[1695] Additional pharmaceutical agents that contain a vitamin and/or mineral supplement that can be prepared in a solid dosage form described herein include one or more of the following a vitamin and/or mineral supplements: Vitamin A, Biotin, Vitamin B1 (Thiamin), Vitamin B12, Vitamin B6, Calcium, Choline, Chromium, Copper, Vitamin C, Vitamin D (e.g., Vitamin D3), Vitamin E, Fluoride, Folate, Iodine, Iron, Vitamin K, Magnesium, Manganese, Niacin, Pantothenic Acid, Phosphorus, Potassium, Riboflavin, Selenium, Thiamin, and/or Zinc.
[1696] Additional pharmaceutical agents that contain a dietary supplement (e.g., a vitamin, a mineral, an herb, an amino acid, an oil, and/or an enzyme) that can be prepared in a solid dosage form described herein include one or more of the following dietary supplements: acacia rigidula, BMPEA, DMAA, DMBA, DMHA, methylsynephrine, phenibut, picamilon, caffeine, tianeptine, vinpocetine, fish oil, flaxseed oil, omega-3, omega-6, omega-9, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and/or alpha-linolenic acid (ALA).
[1697] The dose of the additional pharmaceutical agent in the solid dosage form (e.g., wherein the dose is per capsule or tablet or total per total number of minitablets used in a capsule) can be a dose described herein for a pharmaceutical agent that comprises bacteria and/or mEVs.
[1698] The dose of the additional pharmaceutical agent in the solid dosage form (e.g., wherein the dose is per capsule or tablet or total per total number of minitablets used in a capsule) can be, e.g., about 0.001 mg to about 10 mg fixed dose (e.g., about 0.05 mg to about 10 mg; about 0.1 mg to about 10 mg; about 0.1 mg to about 5 mg; about 0.5 mg to about 5 mg; about lmg, about 2mg, about 3mg, about 4mg, or about 5 mg).
[1699] The dose of the additional pharmaceutical agent in the solid dosage form (e.g., wherein the dose is per capsule or tablet or total per total number of minitablets used in a capsule) can be, particularly for a supplement, e.g., about 1 mg to about 2000 mg (e.g., about 25 mg; about 50 mg; about 100 mg; about 250 mg; about 500 mg; about 750 mg;
about 1000 mg; about 1500 mg; or about 2000 mg) or about 10 IU to about 5000 IU
(international units) (e.g., about 25 IU; about 50 IU; about 100 IU; about 250 IU; about 500 IU; about 750 IU; about 1000 IU; about 1500 IU; about 2000 IU; about 3000 IU;
about 4000 IU; or about 5000 IU).
Additional Pharmaceutical agents for Combination Use [1700] In certain aspects, the methods provided herein include the administration to a subject of a solid dosage form described herein either alone or in combination with an additional pharmaceutical agent. In some embodiments, the additional pharmaceutical agent is an immunosuppressant, an anti-inflammatory agent, a steroid, and/or a cancer therapeutic.
[1701] In some embodiments, the solid dosage form is administered to the subject before the additional pharmaceutical agent is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before). In some embodiments , the solid dosage form is administered to the subject after the additional pharmaceutical agent is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours after or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days after). In some embodiments, the solid dosage form and the additional pharmaceutical agent are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other).
[1702] In some embodiments, an antibiotic is administered to the subject before the solid dosage form is administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before). In some embodiments, an antibiotic is administered to the subject after the solid dosage form is administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days after).
In some embodiments, the solid dosage form and the antibiotic are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other).
[1703] In some embodiments, the additional pharmaceutical agent is a cancer therapeutic. In some embodiments, the cancer therapeutic is a chemotherapeutic agent.
Examples of such chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa;
ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine;
acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;
nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine;
antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammalI
and calicheamicin omegall; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane;
folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside;
aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene;
edatraxate; defofamine;
demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone;
etoglucid;
gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin;
phenamet;
pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine;
PSK
polysaccharide complex); razoxane; rhizoxin; sizofuran; spirogermanium;
tenuazonic acid;
triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine;
mitobronitol;
mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide;
thiotepa;
taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine;
mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);
ifosfamide;
mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate;
daunomycin;
aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS
2000; difluoromethylomithine (DMF0); retinoids such as retinoic acid;
capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[1704] In some embodiments, the cancer therapeutic is a cancer immunotherapy agent. Immunotherapy refers to a treatment that uses a subject's immune system to treat cancer, e.g., checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cells, and dendritic cell therapy. Non-limiting examples of immunotherapies are checkpoint inhibitors include Nivolumab (BMS, anti-PD-1), Pembrolizumab (Merck, anti-PD-1), Ipilimumab (BMS, anti-CTLA-4), 1V1EDI4736 (AstraZeneca, anti-PD-L1), and MPDL3280A (Roche, anti-PD-L1). Other immunotherapies may be tumor vaccines, such as Gardail, Cervarix, BCG, sipulencel-T, Gp100:209-217, AGS-003, DCVax-L, Algenpantucel-L, Tergenpantucel-L, TG4010, ProstAtak, Prostvac-V/R-TRICOM, Rindopepimul, E75 peptide acetate, IMA901, POL-103A, Belagenpumatucel-L, GSK1572932A, MDX-1279, GV1001, and Tecemotide. The immunotherapy agent may be administered via injection (e.g., intravenously, intratumorally, subcutaneously, or into lymph nodes), but may also be administered orally, topically, or via aerosol.
Immunotherapies may comprise adjuvants such as cytokines.
[1705] In some embodiments, the immunotherapy agent is an immune checkpoint inhibitor. Immune checkpoint inhibition broadly refers to inhibiting the checkpoints that cancer cells can produce to prevent or downregulate an immune response.
Examples of immune checkpoint proteins include, but are not limited to, CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3 or VISTA. Immune checkpoint inhibitors can be antibodies or antigen binding fragments thereof that bind to and inhibit an immune checkpoint protein. Examples of immune checkpoint inhibitors include, but are not limited to, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG-7446, BMS-936559, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010.
[1706] In some embodiments, the methods provided herein include the administration of a pharmaceutical composition described herein in combination with one or more additional pharmaceutical agents. In some embodiments, the methods disclosed herein include the administration of two immunotherapy agents (e.g., immune checkpoint inhibitor). For example, the methods provided herein include the administration of a pharmaceutical composition described herein in combination with a PD-1 inhibitor (such as pemrolizumab or nivolumab or pidilizumab) or a CLTA-4 inhibitor (such as ipilimumab) or a PD-Li inhibitor.

[1707] In some embodiments, the immunotherapy agent is an antibody or antigen binding fragment thereof that, for example, binds to a cancer-associated antigen. Examples of cancer-associated antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1, BCLX
(L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH
(hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gp100/Pme117, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, ID01, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-A10, MAGE-Al2, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan-A/MART-1, Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY-BR-1, NY-ES0-1/LAGE-2, 0A1, OGT, 0S-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -55X2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-1/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE-lb/GAGED2a. In some embodiments, the antigen is a neo-antigen.
[1708] In some embodiments, the immunotherapy agent is a cancer vaccine and/or a component of a cancer vaccine (e.g., an antigenic peptide and/or protein). The cancer vaccine can be a protein vaccine, a nucleic acid vaccine or a combination thereof. For example, in some embodiments, the cancer vaccine comprises a polypeptide comprising an epitope of a cancer-associated antigen. In some embodiments, the cancer vaccine comprises a nucleic acid (e.g., DNA or RNA, such as mRNA) that encodes an epitope of a cancer-associated antigen. Examples of cancer-associated antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1, BCLX (L), BCR-ABL fusion protein b3a2, beta-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, Cyclin-Al, dek-can fusion protein, DKK1, EFTUD2, Elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gp100/Pme117, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL, HLA-All, HLA-A2, HLA-DOB, hsp70-2, ID01, IGF2B3, IL13Ralpha2, Intestinal carboxyl esterase, K-ras, Kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferaseAS
fusion protein, Lengsin, M-CSF, MAGE-Al, MAGE-A10, MAGE-Al2, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, Melan-A/MART-1, Meloe, Midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, Myosin, Myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY-BR-1, NY-ES0-1/LAGE-2, 0A1, OGT, 0S-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38/NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -55X2 fusion protein, TAG-1, TAG-2, Telomerase, TGF-betaRII, TPBG, TRAG-3, Triosephosphate isomerase, TRP-1/gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE-lb/GAGED2a. In some embodiments, the antigen is a neo-antigen. In some embodiments, the cancer vaccine is administered with an adjuvant. Examples of adjuvants include, but are not limited to, an immune modulatory protein, Adjuvant 65, a-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, 13-Glucan Peptide, CpG ODN DNA, GPI-0100, lipid A, lipopolysaccharide, Lipovant, Montanide, N-acetyl-muramyl-L-alanyl-D-isoglutamine, Pam3CSK4, quil A, cholera toxin (CT) and heat-labile toxin from enterotoxigenic Escherichia coil (LT) including derivatives of these (CTB, mmCT, CTAl-DD, LTB, LTK63, LTR72, dmLT) and trehalose dimycolate.

[1709] In some embodiments, the immunotherapy agent is an immune modulating protein to the subject. In some embodiments, the immune modulatory protein is a cytokine or chemokine. Examples of immune modulating proteins include, but are not limited to, B
lymphocyte chemoattractant ("BLC"), C-C motif chemokine 11 ("Eotaxin-1"), Eosinophil chemotactic protein 2 ("Eotaxin-2"), Granulocyte colony-stimulating factor ("G-CSF"), Granulocyte macrophage colony-stimulating factor ("GM-CSF"), 1-309, Intercellular Adhesion Molecule 1 ("ICAM-1"), Interferon alpha ("IFN-alpha"), Interferon beta ("IFN-beta") Interferon gamma ("IFN-gamma"), Interlukin-1 alpha ("IL-1 alpha"), Interlukin-1 beta ("IL-1 beta"), Interleukin 1 receptor antagonist ("IL-1 ra"), Interleukin-2 ("IL-2"), Interleukin-4 ("IL-4"), Interleukin-5 ("IL-5"), Interleukin-6 ("IL-6"), Interleukin-6 soluble receptor ("IL-6 sR"), Interleukin-7 ("IL-7"), Interleukin-8 ("IL-8"), Interleukin- 10 ("IL-10"), Interleukin- 11 ("IL-11"), Subunit beta of Interleukin- 12 ("IL-12 p40"
or "IL-12 p'70"), Interleukin-13 ("IL-13"), Interleukin-15 ("IL-15"), Interleukin-16 ("IL-16"), Interleukin-17A-F ("IL-17A-F"), Interleukin-18 ("IL-18"), Interleukin-21 ("IL-21"), Interleukin-22 ("IL-22"), Interleukin-23 ("IL-23"), Interleukin-33 ("IL-33"), Chemokine (C-C motif) Ligand 2 ("MCP-1"), Macrophage colony-stimulating factor ("M-CSF"), Monokine induced by gamma interferon ("MIG"), Chemokine (C-C motif) ligand 2 ("MIP-1 alpha"), Chemokine (C-C motif) ligand 4 ("MIP-1 beta"), Macrophage inflammatory protein- 1 -delta ("MIP-1 delta"), Platelet-derived growth factor subunit B
("PDGF-BB"), Chemokine (C-C motif) ligand 5, Regulated on Activation, Normal T cell Expressed and Secreted ("RANTES"), TIMP metallopeptidase inhibitor 1 ("TIMP-1"), TIMP
metallopeptidase inhibitor 2 ("TIMP-2"), Tumor necrosis factor, lymphotoxin-alpha ("TNF
alpha"), Tumor necrosis factor, lymphotoxin-beta ("TNF beta"), Soluble TNF
receptor type 1 ("sTNFRI"), sTNFRIIAR, Brain-derived neurotrophic factor ("BDNF"), Basic fibroblast growth factor ("bFGF"), Bone morphogenetic protein 4 ("BMP-4"), Bone morphogenetic protein 5 ("BMP-5"), Bone morphogenetic protein 7 ("BlVIP-7"), Nerve growth factor ("b-NGF"), Epidermal growth factor ("EGF"), Epidermal growth factor receptor ("EGFR"), Endocrine-gland-derived vascular endothelial growth factor ("EG-VEGF"), Fibroblast growth factor 4 ("FGF-4"), Keratinocyte growth factor ("FGF-7"), Growth differentiation factor 15 ("GDF-15"), Glial cell-derived neurotrophic factor ("GDNF"), Growth Hormone, Heparin-binding EGF-like growth factor ("HB-EGF"), Hepatocyte growth factor ("HGF"), Insulin-like growth factor binding protein 1 ("IGFBP-1"), Insulin-like growth factor binding protein 2 ("IGFBP-2"), Insulin-like growth factor binding protein 3 (" IGFBP-3"), Insulin-like growth factor binding protein 4 ("IGFBP-4"), Insulin-like growth factor binding protein 6 ("IGFBP-6"), Insulin-like growth factor 1 ("IGF-1"), Insulin, Macrophage colony-stimulating factor ("M-CSF R"), Nerve growth factor receptor ("NGF R"), Neurotrophin-3 ("NT-3"), Neurotrophin-4 ("NT-4"), Osteoclastogenesis inhibitory factor ("Osteoprotegerin"), Platelet-derived growth factor receptors ("PDGF-AA"), Phosphatidylinositol-glycan biosynthesis ("PIGF"), Skp, Cullin, F-box containing comples ("SCF"), Stem cell factor receptor ("SCF R"), Transforming growth factor alpha ("TGFalpha"), Transforming growth factor beta-1 ("TGF beta 1"), Transforming growth factor beta-3 ("TGF beta 3"), Vascular endothelial growth factor ("VEGF"), Vascular endothelial growth factor receptor 2 ("VEGFR2"), Vascular endothelial growth factor receptor 3 ("VEGFR3"), VEGF-D 6Ckine, Tyrosine-protein kinase receptor UFO
("Ax1"), Betacellulin ("BTC"), Mucosae-associated epithelial chemokine ("CCL28"), Chemokine (C-C motif) ligand 27 ("CTACK"), Chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif chemokine 5 ("ENA-78"), Chemokine (C-C motif) ligand 26 ("Eotaxin-3"), Granulocyte chemotactic protein 2 ("GCP-2"), GRO, Chemokine (C-C motif) ligand ("HCC-1"), Chemokine (C-C motif) ligand 16 ("HCC-4"), Interleukin-9 ("IL-9"), Interleukin-17 F ("IL-17F"), Interleukin- 18-binding protein ("IL-18 BPa"), Interleukin-28 A ("IL-28A"), Interleukin 29 ("IL-29"), Interleukin 31 ("IL-31"), C-X-C motif chemokine ("IP-10"), Chemokine receptor CXCR3 ("I-TAC"), Leukemia inhibitory factor ("LIF"), Light, Chemokine (C motif) ligand ("Lymphotactin"), Monocyte chemoattractant protein 2 ("MCP-2"), Monocyte chemoattractant protein 3 ("MCP-3"), Monocyte chemoattractant protein 4 ("MCP-4"), Macrophage-derived chemokine ("MDC"), Macrophage migration inhibitory factor ("MIF"), Chemokine (C-C motif) ligand 20 ("MIP-3 alpha"), C-C motif chemokine 19 ("MIP-3 beta"), Chemokine (C-C motif) ligand 23 ("MPIF-1"), Macrophage stimulating protein alpha chain ("MSPalpha"), Nucleosome assembly protein 1-like 4 ("NAP-2"), Secreted phosphoprotein 1 ("Osteopontin"), Pulmonary and activation-regulated cytokine ("PARC"), Platelet factor 4 ("PF4"), Stroma cell-derived factor- 1 alpha ("SDF-1 alpha"), Chemokine (C-C motif) ligand 17 ("TARC"), Thymus-expressed chemokine ("TECK"), Thymic stromal lymphopoietin ("TSLP 4- IBB"), CD 166 antigen ("ALCAM"), Cluster of Differentiation 80 ("B7-1"), Tumor necrosis factor receptor superfamily member 17 ("BCMA"), Cluster of Differentiation 14 ("CD14"), Cluster of Differentiation 30 ("CD30"), Cluster of Differentiation 40 ("CD40 Ligand"), Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) ("CEACAM-1"), Death Receptor 6 ("DR6"), Deoxythymidine kinase ("Dtk"), Type 1 membrane glycoprotein ("Endoglin"), Receptor tyrosine-protein kinase erbB-3 ("ErbB3"), Endothelial-leukocyte adhesion molecule 1 ("E-Selectin"), Apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), Tumor necrosis factor receptor superfamily member 1 ("GITR"), Tumor necrosis factor receptor superfamily member 14 ("HVEM"), Intercellular adhesion molecule 3 ("ICAM-3"), IL-1 R4, IL-1 RI, IL-10 Rbeta, IL-17R, IL-2Rgamma, IL-21R, Lysosome membrane protein 2 ("LIMPII"), Neutrophil gelatinase-associated lipocalin ("Lipocalin-2"), CD62L ("L-Selectin"), Lymphatic endothelium ("LYVE-1"), MHC class I polypeptide-related sequence A ("MICA"), MHC class I
polypeptide-related sequence B ("MICB"), NRG1-betal, Beta-type platelet-derived growth factor receptor ("PDGF Rbeta"), Platelet endothelial cell adhesion molecule ("PECAM-1"), RAGE, Hepatitis A virus cellular receptor 1 ("TIM-1"), Tumor necrosis factor receptor superfamily member IOC ("TRAIL R3"), Trappin protein transglutaminase binding domain ("Trappin-2"), Urokinase receptor ("uPAR"), Vascular cell adhesion protein 1 ("VCAM-1"), XEDARActivin A, Agouti-related protein ("AgRP"), Ribonuclease 5 ("Angiogenin"), Angiopoietin 1, Angiostatin, Catheprin S, CD40, Cryptic family protein IB
("Cripto-1"), DAN, Dickkopf-related protein 1 ("DKK-1"), E-Cadherin, Epithelial cell adhesion molecule ("EpCAM"), Fas Ligand (FasL or CD95L), Fcg RIIB/C, FoUistatin, Galectin-7, Intercellular adhesion molecule 2 ("ICAM-2"), IL-13 R1, IL-13R2, IL-17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, Neuronal cell adhesion molecule ("NrCAM"), Plasminogen activator inhibitor- 1 ("PAI-1"), Platelet derived growth factor receptors ("PDGF-AB"), Resistin, stromal cell-derived factor 1 ("SDF-1 beta"), sgp130, Secreted frizzled-related protein 2 ("ShhN"), Sialic acid-binding immunoglobulin-type lectins ("Siglec-5"), 5T2, Transforming growth factor-beta 2 ("TGF beta 2"), Tie-2, Thrombopoietin ("TPO"), Tumor necrosis factor receptor superfamily member 10D ("TRAIL R4"), Triggering receptor expressed on myeloid cells 1 ("TREM-1"), Vascular endothelial growth factor C
("VEGF-C"), VEGFR1Adiponectin, Adipsin ("AND"), Alpha-fetoprotein ("AFP"), Angiopoietin-like 4 ("ANGPTL4"), Beta-2-microglobulin ("B2M"), Basal cell adhesion molecule ("BCAM"), Carbohydrate antigen 125 ("CA125"), Cancer Antigen 15-3 ("CA15-3"), Carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), Human Epidermal Growth Factor Receptor 2 ("ErbB2"), Follistatin, Follicle-stimulating hormone ("FSH"), Chemokine (C-X-C motif) ligand 1 ("GRO alpha"), human chorionic gonadotropin ("beta HCG"), Insulin-like growth factor 1 receptor ("IGF-1 sR"), IL-1 sRII, IL-3, IL-18 Rb, IL-21, Leptin, Matrix metalloproteinase-1 ("MMP-1"), Matrix metalloproteinase-2 ("MMP-2"), Matrix metalloproteinase-3 ("MMP-3"), Matrix metalloproteinase-8 ("MMP-8"), Matrix metalloproteinase-9 ("MMP-9"), Matrix metalloproteinase-10 ("MMP-10"), Matrix metalloproteinase-13 ("MMP-13"), Neural Cell Adhesion Molecule ("NCAM-1"), Entactin ("Nidogen-1"), Neuron specific enolase ("NSE"), Oncostatin M ("OSM"), Procalcitonin, Prolactin, Prostate specific antigen ("PSA"), Sialic acid-binding Ig-like lectin 9 ("Siglec-9"), ADAM 17 endopeptidase ("TACE"), Thyroglobulin, Metalloproteinase inhibitor 4 ("TIMP-4"), TSH2B4, Disintegrin and metalloproteinase domain-containing protein 9 ("ADAM-9"), Angiopoietin 2, Tumor necrosis factor ligand superfamily member Acidic leucine-rich nuclear phosphoprotein 32 family member B ("APRIL"), Bone morphogenetic protein 2 ("BMP-2"), Bone morphogenetic protein 9 ("BMP-9"), Complement component 5a ("C5a"), Cathepsin L, CD200, CD97, Chemerin, Tumor necrosis factor receptor superfamily member 6B ("DcR3"), Fatty acid-binding protein 2 ("FABP2"), Fibroblast activation protein, alpha ("FAP"), Fibroblast growth factor 19 ("FGF-19"), Galectin-3, Hepatocyte growth factor receptor ("HGF R"), IFN-gammalpha/beta R2, Insulin-like growth factor 2 ("IGF-2"), Insulin-like growth factor 2 receptor ("IGF-2 R"), Interleukin-1 receptor 6 ("IL-1R6"), Interleukin 24 ("IL-24"), Interleukin 33 ("IL-33", Kallikrein 14, Asparaginyl endopeptidase ("Legumain"), Oxidized low-density lipoprotein receptor 1 ("LOX-1"), Mannose-binding lectin ("MBL"), Neprilysin ("NEP"), Notch homolog 1, translocation-associated (Drosophila) ("Notch-1"), Nephroblastoma overexpressed ("NOV"), Osteoactivin, Programmed cell death protein 1 ("PD-1"), N-acetylmuramoyl-L-alanine amidase ("PGRP-5"), Serpin A4, Secreted frizzled related protein 3 ("sFRP-3"), Thrombomodulin, Tolllike receptor 2 ("TLR2"), Tumor necrosis factor receptor superfamily member 10A ("TRAIL R1"), Transferrin ("TRF"), WIF-1ACE-2, Albumin, AMICA, Angiopoietin 4, B-cell activating factor ("BAFF"), Carbohydrate antigen 19-9 ("CA19-9"), CD 163 , Clusterin, CRT AM, Chemokine (C-X-C
motif) ligand 14 ("CXCL14"), Cystatin C, Decorin ("DCN"), Dickkopf-related protein 3 ("Dkk-3"), Delta-like protein 1 ("DLL1"), Fetuin A, Heparin-binding growth factor 1 ("aFGF"), Folate receptor alpha ("FOLR1"), Furin, GPCR-associated sorting protein 1 ("GASP-1"), GPCR-associated sorting protein 2 ("GASP-2"), Granulocyte colony-stimulating factor receptor ("GCSF R"), Serine protease hepsin ("HAI-2"), Interleukin-17B
Receptor ("IL-17B R"), Interleukin 27 ("IL-27"), Lymphocyte-activation gene 3 ("LAG-3"), Apolipoprotein A-V ("LDL R"), Pepsinogen I, Retinol binding protein 4 ("RBP4"), SOST, Heparan sulfate proteoglycan ("Syndecan-1"), Tumor necrosis factor receptor superfamily member 13B ("TACT"), Tissue factor pathway inhibitor ("TFPI"), TSP-1, Tumor necrosis factor receptor superfamily, member 10b ("TRAIL R2"), TRANCE, Troponin I, Urokinase Plasminogen Activator ("uPA"), Cadherin 5, type 2 or VE-cadherin (vascular endothelial) also known as CD144 ("VE-Cadherin"), WNT1-inducible-signaling pathway protein 1 ("WISP-1"), and Receptor Activator of Nuclear Factor lc B
("RANK").
[1710] In some embodiments, the cancer therapeutic is an anti-cancer compound.
Exemplary anti-cancer compounds include, but are not limited to, Alemtuzumab (Campathg), Alitretinoin (Panreting), Anastrozole (Arimidexg), Bevacizumab (Avasting), Bexarotene (Targreting), Bortezomib (Velcadeg), Bosutinib (Bosulifg), Brentuximab vedotin (Adcetrisg), Cabozantinib (CometriqTm), Carfilzomib (KyprolisTm), Cetuximab (Erbituxg), Crizotinib (Xalkorig), Dasatinib (Sprycelg), Denileukin diftitox (Ontakg), Erlotinib hydrochloride (Tarcevag), Everolimus (Afinitorg), Exemestane (Aromasing), Fulvestrant (Faslodexg), Gefitinib (Iressag), Ibritumomab tiuxetan (Zevaling), Imatinib mesylate (Gleevecg), Ipilimumab (YervoyTm), Lapatinib ditosylate (Tykerbg), Letrozole (Femarag), Nilotinib (Tasignag), Ofatumumab (Arzerrag), Panitumumab (Vectibixg), Pazopanib hydrochloride (Votrientg), Pertuzumab (PerjetaTm), Pralatrexate (Folotyng), Regorafenib (Stivargag), Rituximab (Rituxang), Romidepsin (Istodaxg), Sorafenib tosylate (Nexavarg), Sunitinib malate (Sutentg), Tamoxifen, Temsirolimus (Toriselg), Toremifene (Farestong), Tositumomab and 131I-tositumomab (Bexxarg), Trastuzumab (Hercepting), Tretinoin (Vesanoidg), Vandetanib (Caprelsag), Vemurafenib (Zelborafg), Vorinostat (Zolinzag), and Ziv-aflibercept (Zaltrapg).
[1711] Exemplary anti-cancer compounds that modify the function of proteins that regulate gene expression and other cellular functions (e.g., HDAC inhibitors, retinoid receptor ligants) are Vorinostat (Zolinzag), Bexarotene (Targreting) and Romidepsin (Istodaxg), Alitretinoin (Panreting), and Tretinoin (Vesanoidg).
[1712] Exemplary anti-cancer compounds that induce apoptosis (e.g., proteasome inhibitors, antifolates) are Bortezomib (Velcadeg), Carfilzomib (KyprolisTm), and Pralatrexate (Folotyng).
[1713] Exemplary anti-cancer compounds that increase anti-tumor immune response (e.g., anti CD20, anti CD52; anti-cytotoxic T-lymphocyte-associated antigen-4) are Rituximab (Rituxang), Alemtuzumab (Campathg), Ofatumumab (Arzerrag), and Ipilimumab (YervoyTm).

[1714] Exemplary anti-cancer compounds that deliver toxic agents to cancer cells (e.g., anti-CD20-radionuclide fusions; IL-2-diphtheria toxin fusions; anti-monomethylauristatin E (MMAE)-fusions) are Tositumomab and 131I-tositumomab (Bexxarg)and Ibritumomab tiuxetan (Zevaling), Denileukin diftitox (Ontakg), and Brentuximab vedotin (Adcetrisg).
[1715] Other exemplary anti-cancer compounds are small molecule inhibitors and conjugates thereof of, e.g., Janus kinase, ALK, Bc1-2, PARP, PI3K, VEGF
receptor, Braf, MEK, CDK, and HSP90.
[1716] Exemplary platinum-based anti-cancer compounds include, for example, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, Nedaplatin, Triplatin, and Lipoplatin. Other metal-based drugs suitable for treatment include, but are not limited to ruthenium-based compounds, ferrocene derivatives, titanium-based compounds, and gallium-based compounds.
[1717] In some embodiments, the cancer therapeutic is a radioactive moiety that comprises a radionuclide. Exemplary radionuclides include, but are not limited to Cr-51, Cs-131, Ce-134, Se-75, Ru-97, 1-125, Eu-149, Os-189m, Sb-119, 1-123, Ho-161, Sb-117, Ce-139, In-111, Rh-103m, Ga-67, T1-201, Pd-103, Au-195, Hg-197, Sr-87m, Pt-191, P-33, Er-169, Ru-103, Yb-169, Au-199, Sn-121, Tm-167, Yb-175, In-113m, Sn-113, Lu-177, Rh-105, Sn-117m, Cu-67, Sc-47, Pt-195m, Ce-141, 1-131, Tb-161, As-77, Pt-197, Sm-153, Gd-159, Tm-173, Pr-143, Au-198, Tm-170, Re-186, Ag-111, Pd-109, Ga-73, Dy-165, Pm-149, Sn-123, Sr-89, Ho-166, P-32, Re-188, Pr-142, Ir-194, In-114m/In-114, and Y-90.
[1718] In some embodiments, the cancer therapeutic is an antibiotic. For example, if the presence of a cancer-associated bacteria and/or a cancer-associated microbiome profile is detected according to the methods provided herein, antibiotics can be administered to eliminate the cancer-associated bacteria from the subject. "Antibiotics"
broadly refers to compounds capable of inhibiting or preventing a bacterial infection.
Antibiotics can be classified in a number of ways, including their use for specific infections, their mechanism of action, their bioavailability, or their spectrum of target microbe (e.g., Gram-negative vs.
Gram-positive bacteria, aerobic vs. anaerobic bacteria, etc.) and these may be used to kill specific bacteria in specific areas of the host ("niches") (Leekha, et al 2011. General Principles of Antimicrobial Therapy. Mayo Clin Proc. 86(2): 156-167). In certain embodiments, antibiotics can be used to selectively target bacteria of a specific niche. In some embodiments, antibiotics known to treat a particular infection that includes a cancer niche may be used to target cancer-associated microbes, including cancer-associated bacteria in that niche. In other embodiments, antibiotics are administered after the solid dosage form. In some embodiments, antibiotics are administered before the solid dosage form.
[1719] In some aspects, antibiotics can be selected based on their bactericidal or bacteriostatic properties. Bactericidal antibiotics include mechanisms of action that disrupt the cell wall (e.g., 13-lactams), the cell membrane (e.g., daptomycin), or bacterial DNA (e.g., fluoroquinolones). B acteriostatic agents inhibit bacterial replication and include sulfonamides, tetracyclines, and macrolides, and act by inhibiting protein synthesis.
Furthermore, while some drugs can be bactericidal in certain organisms and bacteriostatic in others, knowing the target organism allows one skilled in the art to select an antibiotic with the appropriate properties. In certain treatment conditions, bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics. Thus, in certain embodiments, bactericidal and bacteriostatic antibiotics are not combined.
[1720] Antibiotics include, but are not limited to aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, and anti-mycobacterial compounds, and combinations thereof.
[1721] Aminoglycosides include, but are not limited to Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, and Spectinomycin.
Aminoglycosides are effective, e.g., against Gram-negative bacteria, such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa, and Francisella tularensis, and against certain aerobic bacteria but less effective against obligate/facultative anaerobes.
Aminoglycosides are believed to bind to the bacterial 30S or 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.
[1722] Ansamycins include, but are not limited to, Geldanamycin, Herbimycin, Rifamycin, and Streptovaricin. Geldanamycin and Herbimycin are believed to inhibit or alter the function of Heat Shock Protein 90.
[1723] Carbacephems include, but are not limited to, Loracarbef.
Carbacephems are believed to inhibit bacterial cell wall synthesis.
[1724] Carbapenems include, but are not limited to, Ertapenem, Doripenem, Imipenem/Cilastatin, and Meropenem. Carbapenems are bactericidal for both Gram-positive and Gram-negative bacteria as broad-spectrum antibiotics. Carbapenems are believed to inhibit bacterial cell wall synthesis.
[1725] Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin, Cefalotin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil,and Ceftobiprole.
Selected Cephalosporins are effective, e.g., against Gram-negative bacteria and against Gram-positive bacteria, including Pseudomonas, certain Cephalosporins are effective against methicillin-resistant Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
[1726] Glycopeptides include, but are not limited to, Teicoplanin, Vancomycin, and Telavancin. Glycopeptides are effective, e.g., against aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile. Glycopeptides are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
[1727] Lincosamides include, but are not limited to, Clindamycin and Lincomycin.
Lincosamides are effective, e.g., against anaerobic bacteria, as well as Staphylococcus, and Streptococcus. Lincosamides are believed to bind to the bacterial 50S
ribosomal subunit thereby inhibiting bacterial protein synthesis.
[1728] Lipopeptides include, but are not limited to, Daptomycin.
Lipopeptides are effective, e.g., against Gram-positive bacteria. Lipopeptides are believed to bind to the bacterial membrane and cause rapid depolarization.
[1729] Macrolides include, but are not limited to, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, and Spiramycin. Macrolides are effective, e.g., against Streptococcus and Mycoplasma.
Macrolides are believed to bind to the bacterial or 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.
[1730] Monobactams include, but are not limited to, Aztreonam.
Monobactams are effective, e.g., against Gram-negative bacteria. Monobactams are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
[1731] Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.

[1732] Oxazolidonones include, but are not limited to, Linezolid, Posizolid, Radezolid, and Torezolid. Oxazolidonones are believed to be protein synthesis inhibitors.
[1733] Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin and Ticarcillin.
Penicillins are effective, e.g., against Gram-positive bacteria, facultative anaerobes, e.g., Streptococcus, Borrelia, and Treponema. Penicillins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.
[1734] Penicillin combinations include, but are not limited to, Amoxicillin/clavulanate, Ampicillin/sulbactam, Piperacillin/tazobactam, and Ticarcillin/clavulanate.
[1735] Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and Polymyxin B and E. Polypeptide Antibiotics are effective, e.g., against Gram-negative bacteria. Certain polypeptide antibiotics are believed to inhibit isoprenyl pyrophosphate involved in synthesis of the peptidoglycan layer of bacterial cell walls, while others destabilize the bacterial outer membrane by displacing bacterial counter-ions.
[1736] Quinolones and Fluoroquinolone include, but are not limited to, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, and Temafloxacin. Quinolones/Fluoroquinolone are effective, e.g., against Streptococcus and Neisseria. Quinolones/Fluoroquinolone are believed to inhibit the bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.
[1737] Sulfonamides include, but are not limited to, Mafenide, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), and Sulfonamidochrysoidine. Sulfonamides are believed to inhibit folate synthesis by competitive inhibition of dihydropteroate synthetase, thereby inhibiting nucleic acid synthesis.
[1738] Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, and Tetracycline. Tetracyclines are effective, e.g., against Gram-negative bacteria. Tetracyclines are believed to bind to the bacterial 30S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[1739] Anti-mycobacterial compounds include, but are not limited to, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine, and Streptomycin.
[1740] Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin Pl, clarithromycin, erythromycins, furazolidone, fusidic acid, Na fusidate, gramicidin, imipenem, indolicidin, josamycin, magainan II, metronidazole, nitroimidazoles, mikamycin, mutacin B-Ny266, mutacin B-JH1 140, mutacin J-T8, nisin, nisin A, novobiocin, oleandomycin, ostreogrycin, piperacillin/tazobactam, pristinamycin, ramoplanin, ranalexin, reuterin, rifaximin, rosamicin, rosaramicin, spectinomycin, spiramycin, staphylomycin, streptogramin, streptogramin A, synergistin, taurolidine, teicoplanin, telithromycin, ticarcillin/clavulanic acid, triacetyloleandomycin, tylosin, tyrocidin, tyrothricin, vancomycin, vemamycin, and virginiamycin.
[1741] In some embodiments, the additional pharmaceutical agent is an immunosuppressive agent, a DMARD, a pain-control drug, a steroid, a non-steroidal antiinflammatory drug (NSAID), or a cytokine antagonist, and combinations thereof Representative agents include, but are not limited to, cyclosporin, retinoids, corticosteroids, propionic acid derivative, acetic acid derivative, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib, ibuprophen, cholin magnesium salicylate, fenoprofen, salsalate, difunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetominophen, Celecoxib, Diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, tolfenamic, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprophen, firocoxib, methotrexate (MTX), antimalarial drugs (e.g., hydroxychloroquine and chloroquine), sulfasalazine, Leflunomide, azathioprine, cyclosporin, gold salts, minocycline, cyclophosphamide, D-penicillamine, minocycline, auranofin, tacrolimus, myocrisin, chlorambucil, TNF alpha antagonists (e.g., TNF alpha antagonists or TNF alpha receptor antagonists), e.g., ADALIMUMAB (Humirag), ETANERCEPT (Enbrelg), INIFLIXIMAB (Remicadeg; TA-650), CERTOLIZUMAB PEGOL (Cimziag; CDP870), GOLEVIUMAB (Simpomg; CNTO 148), ANAKINRA (Kineretg), RITUXIMAB

(Rituxang; MabTherag), ABATACEPT (Orenciag), TOCILIZUMAB (RoActemra /Actemrag), integrin antagonists (TYSABRI (natalizumab)), IL-1 antagonists (ACZ885 (Ilaris)), Anakinra (Kineret )), CD4 antagonists, IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, BLyS antagonists (e.g., Atacicept, Benlystag/ LymphoStat-B
(belimumab)), p38 Inhibitors, CD20 antagonists (Ocrelizumab, Ofatumumab (Arzerra )), interferon gamma antagonists (Fontolizumab), prednisolone, Prednisone, dexamethasone, Cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone, triamcinolone, beclometasome, fludrocortisone, deoxycorticosterone, aldosterone, Doxycycline, vancomycin, pioglitazone, SBI-087, SC10-469, Cura-100, Oncoxin + Viusid, TwHF, Methoxsalen, Vitamin D - ergocalciferol, Milnacipran, Paclitaxel, rosig tazone, Tacrolimus (Prografg), RAD001, rapamune, rapamycin, fostamatinib, Fentanyl, XOMA 052, Fostamatinib disodium,rosightazone, Curcumin (LongvidaTm), Rosuvastatin, Maraviroc, ramipnl, Milnacipran, Cobiprostone, somatropin, tgAAC94 gene therapy vector, MK0359, GW856553, esomeprazole, everolimus, trastuzumab, JAK1 and JAK2 inhibitors, pan JAK
inhibitors, e.g., tetracyclic pyridone 6 (P6), 325, PF-956980, denosumab, IL-6 antagonists, CD20 antagonistis, CTLA4 antagonists, IL-8 antagonists, IL-21 antagonists, IL-antagonist, integrin antagonists (Tysarbri (natalizumab)), VGEF antagnosits, CXCL
antagonists, MMP antagonists, defensin antagonists, IL-1 antagonists (including IL-1 beta antagonsits), and IL-23 antagonists (e.g., receptor decoys, antagonistic antibodies, etc.).
[1742] In some embodiments, the additional pharmaceutical agent is an immunosuppressive agent. Examples of immunosuppressive agents include, but are not limited to, corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergic drugs for rhinitis, TLR antagonists, inflammasome inhibitors, anti-cholinergic decongestants, mast-cell stabilizers, monoclonal anti-IgE
antibodies, vaccines (e.g., vaccines used for vaccination where the amount of an allergen is gradually increased), cytokine inhibitors, such as anti-IL-6 antibodies, TNF
inhibitors such as infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept, iand combinations thereof Administration [1743] In certain aspects, provided herein is a method of delivering a solid dosage form described herein to a subject. In some embodiments of the methods provided herein, the solid dosage form is administered in conjunction with the administration of an additional pharmaceutical agent. In some embodiments, the solid dosage form comprises a pharmaceutical agent that comprises bacteria and/or mEVs co-formulated with the additional pharmaceutical agent. In some embodiments, the solid dosage form is co-administered with the additional pharmaceutical agent. In some embodiments, the additional pharmaceutical agent is administered to the subject before administration of the solid dosage form (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes before, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours before, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days before). In some embodiments, the additional pharmaceutical agent is administered to the subject after administration of the solid dosage form (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes after, about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours after, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after). In some embodiments, the same mode of delivery is used to deliver both the solid dosage form and the additional pharmaceutical agent. In some embodiments, different modes of delivery are used to administer the solid dosage form and the additional pharmaceutical agent. For example, in some embodiments the solid dosage form is administered orally while the additional pharmaceutical agent is administered via injection (e.g., an intravenous, intramuscular and/or intratumoral injection).
[1744] In certain embodiments, the solid dosage form described herein can be administered in conjunction with any other conventional anti-cancer treatment, such as, for example, radiation therapy and surgical resection of the tumor. These treatments may be applied as necessary and/or as indicated and may occur before, concurrent with or after administration of the solid dosage form described herein.
[1745] The dosage regimen can be any of a variety of methods and amounts, and can be determined by one skilled in the art according to known clinical factors. As is known in the medical arts, dosages for any one patient can depend on many factors, including the subject's species, size, body surface area, age, sex, immunocompetence, and general health, the particular microorganism to be administered, duration and route of administration, the kind and stage of the disease, for example, tumor size, and other compounds such as drugs being administered concurrently or near-concurrently. In addition to the above factors, such levels can be affected by the infectivity of the microorganism, and the nature of the microorganism, as can be determined by one skilled in the art. In the present methods, appropriate minimum dosage levels of microorganisms can be levels sufficient for the microorganism to survive, grow and replicate. The dose of a pharmaceutical agent (e.g., in a solid dosage form) described herein may be appropriately set or adjusted in accordance with the dosage form, the route of administration, the degree or stage of a target disease, and the like. For example, the general effective dose of the agents may range between 0.01 mg/kg body weight/day and 1000 mg/kg body weight/day, between 0.1 mg/kg body weight/day and 1000 mg/kg body weight/day, 0.5 mg/kg body weight/day and 500 mg/kg body weight/day, 1 mg/kg body weight/day and 100 mg/kg body weight/day, or between 5 mg/kg body weight/day and 50 mg/kg body weight/day. The effective dose may be 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, or 1000 mg/kg body weight/day or more, but the dose is not limited thereto.
[1746] In some embodiments, the dose administered to a subject is sufficient to prevent disease (e.g., autoimmune disease, inflammatory disease, metabolic disease, dysbiosis, or cancer), delay its onset, or slow or stop its progression, or relieve one or more symptoms of the disease. One skilled in the art will recognize that dosage will depend upon a variety of factors including the strength of the particular agent (e.g., pharmaceutical agent) employed, as well as the age, species, condition, and body weight of the subject. The size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular pharmaceutical agent and the desired physiological effect.
[1747] Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art.
Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound.
Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. An effective dosage and treatment protocol can be determined by routine and conventional means, starting e.g., with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Animal studies are commonly used to determine the maximal tolerable dose ("MTD") of bioactive agent per kilogram weight. Those skilled in the art regularly extrapolate doses for efficacy, while avoiding toxicity, in other species, including humans.
[1748] In accordance with the above, in therapeutic applications, the dosages of the pharmaceutical agents used in accordance with the invention vary depending on the active agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. For example, for cancer treatment, the dose should be sufficient to result in slowing, and preferably regressing, the growth of a tumor and most preferably causing complete regression of the cancer, or reduction in the size or number of metastases. As another example, the dose should be sufficient to result in slowing of progression of the disease for which the subject is being treated, and preferably amelioration of one or more symptoms of the disease for which the subject is being treated.
[1749] Separate administrations can include any number of two or more administrations, including two, three, four, five or six administrations. One skilled in the art can readily determine the number of administrations to perform or the desirability of performing one or more additional administrations according to methods known in the art for monitoring therapeutic methods and other monitoring methods provided herein.
Accordingly, the methods provided herein include methods of providing to the subject one or more administrations of a solid dosage form, where the number of administrations can be determined by monitoring the subject, and, based on the results of the monitoring, determining whether or not to provide one or more additional administrations.
Deciding on whether or not to provide one or more additional administrations can be based on a variety of monitoring results.
[1750] The time period between administrations can be any of a variety of time periods. The time period between administrations can be a function of any of a variety of factors, including monitoring steps, as described in relation to the number of administrations, the time period for a subject to mount an immune response. In one example, the time period can be a function of the time period for a subject to mount an immune response; for example, the time period can be more than the time period for a subject to mount an immune response, such as more than about one week, more than about ten days, more than about two weeks, or more than about a month; in another example, the time period can be less than the time period for a subject to mount an immune response, such as less than about one week, less than about ten days, less than about two weeks, or less than about a month.
[1751] In some embodiments, the delivery of an additional pharmaceutical agent in combination with the solid dosage form described herein reduces the adverse effects and/or improves the efficacy of the additional pharmaceutical agent.
[1752] The effective dose of an additional pharmaceutical agent described herein is the amount of the additional pharmaceutical agent that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, with the least toxicity to the subject. The effective dosage level can be identified using the methods described herein and will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions or agents administered, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts. In general, an effective dose of an additional pharmaceutical agent will be the amount of the additional pharmaceutical agent which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
[1753] The toxicity of an additional pharmaceutical agent is the level of adverse effects experienced by the subject during and following treatment. Adverse events associated with additional therapy toxicity can include, but are not limited to, abdominal pain, acid indigestion, acid reflux, allergic reactions, alopecia, anaphylasix, anemia, anxiety, lack of appetite, arthralgias, asthenia, ataxia, azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, elevated blood pressure, difficulty breathing, bronchitis, bruising, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, hemorrhagic cystitis, arrhythmias, heart valve disease, cardiomyopathy, coronary artery disease, cataracts, central neurotoxicity, cognitive impairment, confusion, conjunctivitis, constipation, coughing, cramping, cystitis, deep vein thrombosis, dehydration, depression, diarrhea, dizziness, dry mouth, dry skin, dyspepsia, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue, loss of fertility, fever, flatulence, flushing, gastric reflux, gastroesophageal reflux disease, genital pain, granulocytopenia, gynecomastia, glaucoma, hair loss, hand-foot syndrome, headache, hearing loss, heart failure, heart palpitations, heartburn, hematoma, hemorrhagic cystitis, hepatotoxicity, hyperamylasemia, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hyperlipasemia, hypermagnesemia, hypernatremia, hyperphosphatemia, hyperpigmentation, hypertriglyceridemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, impotence, infection, injection site reactions, insomnia, iron deficiency, itching, joint pain, kidney failure, leukopenia, liver dysfunction, memory loss, menopause, mouth sores, mucositis, muscle pain, myalgias, myelosuppression, myocarditis, neutropenic fever, nausea, nephrotoxicity, neutropenia, nosebleeds, numbness, ototoxicity, pain, palmar-plantar erythrodysesthesia, pancytopenia, pericarditis, peripheral neuropathy, pharyngitis, photophobia, photosensitivity, pneumonia, pneumonitis, proteinuria, pulmonary embolus, pulmonary fibrosis, pulmonary toxicity, rash, rapid heart beat, rectal bleeding, restlessness, rhinitis, seizures, shortness of breath, sinusitis, thrombocytopenia, tinnitus, urinary tract infection, vaginal bleeding, vaginal dryness, vertigo, water retention, weakness, weight loss, weight gain, and xerostomia. In general, toxicity is acceptable if the benefits to the subject achieved through the therapy outweigh the adverse events experienced by the subject due to the therapy.
Immune Disorders [1754] In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of a disease or disorder associated a pathological immune response, such as an autoimmune disease, an allergic reaction and/or an inflammatory disease. In some embodiments, the disease or disorder is an inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis). In some embodiments, the disease or disorder is psoriasis. In some embodiments, the disease or disorder is atopic dermatitis.
[1755] The methods and solid dosage forms described herein can be used to treat any subject in need thereof. As used herein, a "subject in need thereof' includes any subject that has a disease or disorder associated with a pathological immune response (e.g., an inflammatory bowel disease), as well as any subject with an increased likelihood of acquiring a such a disease or disorder.
[1756] The solid dosage forms described herein can be used, for example, as a pharmaceutical composition for preventing or treating (reducing, partially or completely, the adverse effects of) an autoimmune disease, such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, muckle-wells syndrome, rheumatoid arthritis, multiple sclerosis, or Hashimoto's disease; an allergic disease, such as a food allergy, pollenosis, or asthma; an infectious disease, such as an infection with Clostridium difficile;
an inflammatory disease such as a TNF-mediated inflammatory disease (e.g., an inflammatory disease of the gastrointestinal tract, such as pouchitis, a cardiovascular inflammatory condition, such as atherosclerosis, or an inflammatory lung disease, such as chronic obstructive pulmonary disease); a pharmaceutical composition for suppressing rejection in organ transplantation or other situations in which tissue rejection might occur; a supplement, food, or beverage for improving immune functions; or a reagent for suppressing the proliferation or function of immune cells.
[1757] In some embodiments, the methods and solid dosage forms provided herein are useful for the treatment of inflammation. In certain embodiments, the inflammation of any tissue and organs of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation, as discussed below.
[1758] Immune disorders of the musculoskeletal system include, but are not limited, to those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons. Examples of such immune disorders, which may be treated with the methods and compositions described herein include, but are not limited to, arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic).
[1759] Ocular immune disorders refers to a immune disorder that affects any structure of the eye, including the eye lids. Examples of ocular immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.
[1760] Examples of nervous system immune disorders which may be treated with the methods and solid dosage forms described herein include, but are not limited to, encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis and schizophrenia. Examples of inflammation of the vasculature or lymphatic system which may be treated with the methods and compositions described herein include, but are not limited to, arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.
[1761] Examples of digestive system immune disorders which may be treated with the methods and solid dosage forms described herein include, but are not limited to, cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease, ileitis, and proctitis. Inflammatory bowel diseases include, for example, certain art-recognized forms of a group of related conditions. Several major forms of inflammatory bowel diseases are known, with Crohn's disease (regional bowel disease, e.g., inactive and active forms) and ulcerative colitis (e.g., inactive and active forms) the most common of these disorders. In addition, the inflammatory bowel disease encompasses irritable bowel syndrome, microscopic colitis, lymphocytic-plasmocytic enteritis, coeliac disease, collagenous colitis, lymphocytic colitis and eosinophilic enterocolitis. Other less common forms of IBD include indeterminate colitis, pseudomembranous colitis (necrotizing colitis), ischemic inflammatory bowel disease, Behcet's disease, sarcoidosis, scleroderma, IBD-associated dysplasia, dysplasia associated masses or lesions, and primary sclerosing cholangitis.
[1762] Examples of reproductive system immune disorders which may be treated with the methods and solid dosage forms described herein include, but are not limited to, cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.
[1763] The methods and solid dosage forms described herein may be used to treat autoimmune conditions having an inflammatory component. Such conditions include, but are not limited to, acute disseminated alopecia universalise, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1, giant cell arteritis, goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed connective tissue disease, Muckle-Wells syndrome, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, ord's thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.
[1764] The methods and solid dosage forms described herein may be used to treat T-cell mediated hypersensitivity diseases having an inflammatory component.
Such conditions include, but are not limited to, contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis, house dustmite allergy) and gluten-sensitive enteropathy (Celiac disease).
[1765] Other immune disorders which may be treated with the methods and solid dosage forms include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis, pleuritis, pneumonitis, prostatistis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xengrafts, sewrum sickness, and graft vs host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sexary's syndrome, congenital adrenal hyperplasis, nonsuppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensistivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and oiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) haemolytic anemia, leukaemia and lymphomas in adults, acute leukaemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis. Preferred treatments include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic obstructive pulmonary disease, and inflammation accompanying infectious conditions (e.g., sepsis).

Metabolic Disorders [1766] In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of a metabolic disease or disorder a, such as type II
diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) or a related disease. In some embodiments, the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, or edema. In some embodiments, the methods and pharmaceutical compositions described herein relate to the treatment of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH).
[1767] The methods and solid dosage forms described herein can be used to treat any subject in need thereof. As used herein, a "subject in need thereof' includes any subject that has a metabolic disease or disorder, as well as any subject with an increased likelihood of acquiring a such a disease or disorder.
[1768] The solid dosage forms described herein can be used, for example, for preventing or treating (reducing, partially or completely, the adverse effects of) a metabolic disease, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), Nonalcoholic Steatohepatitis (NASH), or a related disease. In some embodiments, the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, or edema.
[1769]
[1770] Cancer [1771] In some embodiments, the methods and solid dosage forms described herein relate to the treatment of cancer. In some embodiments, any cancer can be treated using the methods described herein. Examples of cancers that may treated by methods and solid dosage forms described herein include, but are not limited to, cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus. In addition, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated;
giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma;
squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma;
transitional cell carcinoma; papillary transitional cell carcinoma;
adenocarcinoma;
gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma;
adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma;
oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma;
granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma;

nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma;
cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma;
mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma;
infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma;
inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma;
adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; and roblastoma, malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant;
paraganglioma, malignant; extra-mammary paraganglioma, malignant;
pheochromocytoma;
glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malig melanoma in giant pigmented nevus; epithelioid cell melanoma;
blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant;
myxosarcoma;
liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma;
alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant;
brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma;
mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma;
hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant;
lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma;
chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone;
ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma;
ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant;
chordoma;
glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma;
fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma;
oligodendroblastoma;
primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma;
neuroblastoma;
retinoblastoma; olfactory neurogenic tumor; meningioma, malignant;
neurofibrosarcoma;
neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma;
Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; malignant lymphoma, small lymphocytic;
malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular;
mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis;
multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease;
leukemia;
lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia;
myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.
[1772] In some embodiments, the cancer comprises breast cancer (e.g., triple negative breast cancer).
[1773] In some embodiments, the cancer comprises colorectal cancer (e.g., microsatellite stable (MSS) colorectal cancer).
[1774] In some embodiments, the cancer comprises renal cell carcinoma.
[1775] In some embodiments, the cancer comprises lung cancer (e.g., non small cell lung cancer).
[1776] In some embodiments, the cancer comprises bladder cancer.
[1777] In some embodiments, the cancer comprises gastroesophageal cancer.
[1778] In some embodiments, the methods and solid dosage forms provided herein relate to the treatment of a leukemia. The term "leukemia" includes broadly progressive, malignant diseases of the hematopoietic organs/systems and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Non-limiting examples of leukemia diseases include, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, and promyelocytic leukemia.
[1779] In some embodiments, the methods and solid dosage forms provided herein relate to the treatment of a carcinoma. The term "carcinoma" refers to a malignant growth made up of epithelial cells tending to infiltrate the surrounding tissues, and/or resist physiological and non-physiological cell death signals and gives rise to metastases. Non-limiting exemplary types of carcinomas include, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, naspharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, and carcinoma scroti.
[1780] In some embodiments, the methods and solid dosage forms provided herein relate to the treatment of a sarcoma. The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar, heterogeneous, or homogeneous substance.
Sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing' s sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.
[1781] Additional exemplary neoplasias that can be treated using the methods and solid dosage forms described herein include Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, plasmacytoma, colorectal cancer, rectal cancer, and adrenal cortical cancer.
[1782] In some embodiments, the cancer treated is a melanoma. The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Non-limiting examples of melanomas are Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma subungal melanoma, and superficial spreading melanoma.
[1783] Particular categories of tumors that can be treated using methods and solid dosage forms described herein include lymphoproliferative disorders, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, stomach cancer, colon cancer, pancreatic cancer, cancer of the thyroid, head and neck cancer, cancer of the central nervous system, cancer of the peripheral nervous system, skin cancer, kidney cancer, as well as metastases of all the above. Particular types of tumors include hepatocellular carcinoma, hepatoma, hepatoblastoma, rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, Ewing's tumor, leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, pulmonary squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (well differentiated, moderately differentiated, poorly differentiated or undifferentiated), bronchioloalveolar carcinoma, renal cell carcinoma, hypernephroma, hypernephroid adenocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, testicular tumor, lung carcinoma including small cell, non-small and large cell lung carcinoma, bladder carcinoma, glioma, astrocyoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, neuroblastoma, colon carcinoma, rectal carcinoma, hematopoietic malignancies including all types of leukemia and lymphoma including: acute myelogenous leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin' s lymphoma, non-Hodgkin' s lymphoma, plasmacytoma, colorectal cancer, and rectal cancer.

[1784] Cancers treated in certain embodiments also include precancerous lesions, e.g., actinic keratosis (solar keratosis), moles (dysplastic nevi), acitinic chelitis (farmer's lip), cutaneous horns, Barrett's esophagus, atrophic gastritis, dyskeratosis congenita, sideropenic dysphagia, lichen planus, oral submucous fibrosis, actinic (solar) elastosis and cervical dysplasia.
[1785] Cancers treated in some embodiments include non-cancerous or benign tumors, e.g., of endodermal, ectodermal or mesenchymal origin, including, but not limited to cholangioma, colonic polyp, adenoma, papilloma, cystadenoma, liver cell adenoma, hydatidiform mole, renal tubular adenoma, squamous cell papilloma, gastric polyp, hemangioma, osteoma, chondroma, lipoma, fibroma, lymphangioma, leiomyoma, rhabdomyoma, astrocytoma, nevus, meningioma, and ganglioneuroma.
Other Diseases and Disorders [1786] In some embodiments, the methods and solid dosage forms described herein relate to the treatment of liver diseases. Such diseases include, but are not limited to, Alagille Syndrome, Alcohol-Related Liver Disease, Alpha-1 Antitrypsin Deficiency, Autoimmune Hepatitis, Benign Liver Tumors, Biliary Atresia, Cirrhosis, Galactosemia, Gilbert Syndrome, Hemochromatosis, Hepatitis A, Hepatitis B, Hepatitis C, Hepatic Encephalopathy, Intrahepatic Cholestasis of Pregnancy (ICP), Lysosomal Acid Lipase Deficiency (LAL-D), Liver Cysts, Liver Cancer, Newborn Jaundice, Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Reye Syndrome, Type I

Glycogen Storage Disease, and Wilson Disease.
[1787] The methods and solid dosage forms described herein may be used to treat neurodegenerative and neurological diseases. In certain embodiments, the neurodegenerative and/or neurological disease is Parkinson's disease, Alzheimer's disease, prion disease, Huntington's disease, motor neuron diseases (MND), spinocerebellar ataxia, spinal muscular atrophy, dystonia, idiopathicintracranial hypertension, epilepsy, nervous system disease, central nervous system disease, movement disorders, multiple sclerosis, encephalopathy, peripheral neuropathy or post-operative cognitive dysfunction.
Dysbiosis [1788] In recent years, it has become increasingly clear that the gut microbiome (also called the "gut microbiota") can have a significant impact on an individual's health through microbial activity and influence (local and/or distal) on immune and other cells of the host (Walker, W.A., Dysbiosis. The Microbiota in Gastrointestinal Pathophysiology.
Chapter 25. 2017; Weiss and Thierry, Mechanisms and consequences of intestinal dysbiosis. Cellular and Molecular Life Sciences. (2017) 74(16):2959-2977.
Zurich Open Repository and Archive, doi: https://doi.org/10.1007/s00018-017-2509-x)).
[1789] A healthy host-gut microbiome homeostasis is sometimes referred to as a "eubiosis" or "normobiosis," whereas a detrimental change in the host microbiome composition and/or its diversity can lead to an unhealthy imbalance in the microbiome, or a "dysbiosis" (Hooks and O'Malley. Dysbiosis and its discontents. American Society for Microbiology. Oct 2017. Vol. 8. Issue 5. mBio 8:e01492-17.
https://doi.org/10.1128/mBio.01492-17). Dysbiosis, and associated local or distal host inflammatory or immune effects, may occur where microbiome homeostasis is lost or diminished, resulting in: increased susceptibility to pathogens; altered host bacterial metabolic activity; induction of host proinflammatory activity and/or reduction of host anti-inflammatory activity. Such effects are mediated in part by interactions between host immune cells (e.g., T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (TEC), macrophages and phagocytes) and cytokines, and other substances released by such cells and other host cells.
[1790] A dysbiosis may occur within the gastrointestinal tract (a "gastrointestinal dysbiosis" or "gut dysbiosis") or may occur outside the lumen of the gastrointestinal tract (a "distal dysbiosis"). Gastrointestinal dysbiosis is often associated with a reduction in integrity of the intestinal epithelial barrier, reduced tight junction integrity and increased intestinal permeability. Citi, S. Intestinal Barriers protect against disease, Science 359:1098-99 (2018); Srinivasan et al., TEER measurement techniques for in vitro barrier model systems. I Lab. Autom. 20:107-126 (2015). A gastrointestinal dysbiosis can have physiological and immune effects within and outside the gastrointestinal tract.
[1791] The presence of a dysbiosis has been associated with a wide variety of diseases and conditions including: infection, cancer, autoimmune disorders (e.g., systemic lupus erythematosus (SLE)) or inflammatory disorders (e.g., functional gastrointestinal disorders such as inflammatory bowel disease (MD), ulcerative colitis, and Crohn's disease), neuroinflammatory diseases (e.g., multiple sclerosis), transplant disorders (e.g., graft-versus-host disease), fatty liver disease, type I diabetes, rheumatoid arthritis, Sjogren's syndrome, celiac disease, cystic fibrosis, chronic obstructive pulmonary disorder (COPD), and other diseases and conditions associated with immune dysfunction. Lynch et al., The Human Microbiome in Health and Disease, N. Engl. I Med .375:2369-79 (2016), Carding et al., Dysbiosis of the gut microbiota in disease. Microb. Ecol. Health Dis.
(2015); 26: 10:
3402/mehd.v26.2619; Levy et al, Dysbiosis and the Immune System, Nature Reviews Immunology 17:219 (April 2017) [1792] Exemplary solid dosage forms disclosed herein can treat a dysbiosis and its effects by modifying the immune activity present at the site of dysbiosis. As described herein, such compositions can modify a dysbiosis via effects on host immune cells, resulting in, e.g., an increase in secretion of anti-inflammatory cytokines and/or a decrease in secretion of pro-inflammatory cytokines, reducing inflammation in the subject recipient or via changes in metabolite production.
[1793] Exemplary solid dosage forms disclosed herein that are useful for treatment of disorders associated with a dysbiosis contain one or more types of immunomodulatory bacteria (e.g., anti-inflammatory bacteria) and/or mEVs (microbial extracellular vesicles) derived from such bacteria. Such compositions are capable of affecting the recipient host's immune function, in the gastrointestinal tract, and/or a systemic effect at distal sites outside the subject's gastrointestinal tract.
[1794] Exemplary solid dosage forms disclosed herein that are useful for treatment of disorders associated with a dysbiosis contain a population of immunomodulatory bacteria of a single bacterial species (e.g., a single strain) (e.g., anti-inflammatory bacteria) and/or mEVs derived from such bacteria. Such compositions are capable of affecting the recipient host's immune function, in the gastrointestinal tract, and /or a systemic effect at distal sites outside the subject's gastrointestinal tract.
[1795] In one embodiment, solid dosage forms containing an isolated population of immunomodulatory bacteria (e.g., anti-inflammatory bacterial cells) and/or mEVs derived from such bacteria are administered (e.g., orally) to a mammalian recipient in an amount effective to treat a dysbiosis and one or more of its effects in the recipient. The dysbiosis may be a gastrointestinal tract dysbiosis or a distal dysbiosis.
[1796] In another embodiment, solid dosage forms of the instant invention can treat a gastrointestinal dysbiosis and one or more of its effects on host immune cells, resulting in an increase in secretion of anti-inflammatory cytokines and/or a decrease in secretion of pro-inflammatory cytokines, reducing inflammation in the subject recipient.

[1797] In another embodiment, the solid dosage forms can treat a gastrointestinal dysbiosis and one or more of its effects by modulating the recipient immune response via cellular and cytokine modulation to reduce gut permeability by increasing the integrity of the intestinal epithelial barrier.
[1798] In another embodiment, the solid dosage forms can treat a distal dysbiosis and one or more of its effects by modulating the recipient immune response at the site of dysbiosis via modulation of host immune cells.
[1799] Other exemplary solid dosage forms are useful for treatment of disorders associated with a dysbiosis, which compositions contain one or more types of bacteria and/or mEVs capable of altering the relative proportions of host immune cell subpopulations, e.g., subpopulations of T cells, immune lymphoid cells, dendritic cells, NK
cells and other immune cells, or the function thereof, in the recipient.
[1800] Other exemplary solid dosage forms are useful for treatment of disorders associated with a dysbiosis, which compositions contain a population of immunomodulatory bacteria and/or mEVs of a single bacterial species, e.g., a single strain) capable of altering the relative proportions of immune cell subpopulations, e.g., T cell subpopulations, immune lymphoid cells, NK cells and other immune cells, or the function thereof, in the recipient subject.
[1801] In one embodiment, the invention provides methods of treating a gastrointestinal dysbiosis and one or more of its effects by orally administering to a subject in need thereof a solid dosage form which alters the microbiome population existing at the site of the dysbiosis. The solid dosage forms can contain one or more types of immunomodulatory bacteria and/or mEVs or a population of immunomodulatory bacteria and/or mEVs of a single bacterial species (e.g., a single strain).
[1802] In one embodiment, the invention provides methods of treating a distal dysbiosis and one or more of its effects by orally administering to a subject in need thereof a solid dosage form which alters the subject's immune response outside the gastrointestinal tract. The solid dosage forms can contain one or more types of immunomodulatory bacteria and/or mEVs or a population of immunomodulatory bacteria and/or mEVs of a single bacterial species (e.g., a single strain).
[1803] In exemplary embodiments, solid dosage forms useful for treatment of disorders associated with a dysbiosis stimulate secretion of one or more anti-inflammatory cytokines by host immune cells. Anti-inflammatory cytokines include, but are not limited to, IL-10, IL-13, IL-9, IL-4, IL-5, TGFO, and combinations thereof. In other exemplary embodiments, solid dosage forms useful for treatment of disorders associated with a dysbiosis that decrease (e.g., inhibit) secretion of one or more pro-inflammatory cytokines by host immune cells. Pro-inflammatory cytokines include, but are not limited to, IFNy, IL-12p'70, IL-la, IL-6, IL-8, MCP1, MIPla, MIP1f3, TNFa, and combinations thereof Other exemplary cytokines are known in the art and are described herein.
[1804] In another aspect, the invention provides a method of treating or preventing a disorder associated with a dysbiosis in a subject in need thereof, comprising administering (e.g., orally administering) to the subject a solid dosage form in the form of a probiotic or medical food comprising bacteria and/or mEVs in an amount sufficient to alter the microbiome at a site of the dysbiosis, such that the disorder associated with the dysbiosis is treated.
[1805] In another embodiment, a solid dosage form of the instant invention in the form of a probiotic or medical food may be used to prevent or delay the onset of a dysbiosis in a subject at risk for developing a dysbiosis.
Methods of Making Enhanced Bacteria [1806] In certain aspects, provided herein are methods of making engineered bacteria for the production of the bacteria and/or mEVs (such as smEVs and/or pmEVs) described herein. In some embodiments, the engineered bacteria are modified to enhance certain desirable properties. For example, in some embodiments, the engineered bacteria are modified to enhance the immunomodulatory and/or therapeutic effect of the bacteria and/or mEVs (such as smEVs and/or pmEVs) (e.g., either alone or in combination with another pharmaceutical agent), to reduce toxicity and/or to improve bacterial and/or mEV (such as smEV and/or pmEV) manufacturing (e.g., higher oxygen tolerance, improved freeze-thaw tolerance, shorter generation times). The engineered bacteria may be produced using any technique known in the art, including but not limited to site-directed mutagenesis, transposon mutagenesis, knock-outs, knock-ins, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light mutagenesis, transformation (chemically or by electroporation), phage transduction, directed evolution, CRISPR/Cas9, or any combination thereof.
[1807] In some embodiments of the methods provided herein, the bacterium is modified by directed evolution. In some embodiments, the directed evolution comprises exposure of the bacterium to an environmental condition and selection of bacterium with improved survival and/or growth under the environmental condition. In some embodiments, the method comprises a screen of mutagenized bacteria using an assay that identifies enhanced bacterium. In some embodiments, the method further comprises mutagenizing the bacteria (e.g., by exposure to chemical mutagens and/or UV radiation) or exposing them to a pharmaceutical agent (e.g., antibiotic) followed by an assay to detect bacteria having the desired phenotype (e.g., an in vivo assay, an ex vivo assay, or an in vitro assay).
Gamma- Irradiation: Sample Protocol:
[1808] Powders are gamma-irradiated at 17.5 kGy radiation unit at ambient temperature. Frozen biomasses are gamma-irradiated at 25 kGy radiation unit in the presence of dry ice.
Frozen Biomass Preparation: Sample Protocol [1809] After a desired level of bacterial culture growth is achieved, centrifuge cultures, discard the supernatant, leaving the pellet as dry as possible.
Vortex the pellet to loosen the biomass. Resuspend pellet in desired cryoprotectant solution, transfer to cryogenic tube and snap freeze in liquid nitrogen. Store in -80 degree C
freezer.
Powder Preparation: Sample Protocol [1810] After desired level of bacterial culture growth is achieved, centrifuge cultures, discard the supernatant, leaving the pellet as dry as possible.
Resuspend pellet in desired cryoprotectant solution to create a formulated cell paste. The cryoprotectant may contain, e.g., maltodextrin, sodium ascorbate, sodium glutamate, and/or calcium chloride.
Load the formulated cell paste onto stainless steel trays and load into a freeze drier, e.g., operating in automated mode with defined cycle parameters. The freeze dried product is fed into a milling machine and the resulting powder is collected.
[1811] Powders are stored (e.g., in vacuum sealed bags) at 2-8 degrees C
(e.g., at 4 degrees C), e.g., in a desiccator.

Examples Example 1: Preparation of Lactococcus lactis spp. Cremoris powder [1812] The fermentation broth was harvested by continuous centrifugation with a flow rate of 2500 L/h and expulsion time of 150 seconds. The concentrated cells were collected and the supernatant is discarded.
[1813] The cryoprotectant solution components were maltodextrin (16%
w/w), sodium ascorbate (8% w/w), sodium glutamate (8% w/w), and calcium chloride (8%
w/w).
They were first dissolved in a mixing tank and pasteurized; the solution was cooled to 4-10 degrees C.
[1814] The cooled cryoprotectant solution was added to the concentrated cells at a ratio of 25% (w/w) and mixed to give a formulated cell paste.
[1815] The formulated cell paste was loaded onto multiple stainless-steel trays. The freeze-drier was operated in an automated mode with defined cycle parameters.
At the end of cycle, the freeze-dried product was removed from the tray and stored in multiple polyethylene bags prior to milling.
[1816] The freeze-dried product was fed into a milling machine and collected into a double polyethylene bags. The bags were checked with a metal detector (given the milling machine is a metal blender) and then stored at 2-8m degrees C prior to final packaging.
[1817] Freeze-dried powder (1 kg aliquots) was placed into a polyethylene bag which was then packed into a PET-AL-PE foil pouch and heat sealed. Long term storage conditions for the finished pouches were 2-8 degrees C.
Example 2: Enteric coated minitablets significantly enhance L. lactis spp.
Cremoris pharmacological activity at low doses [1818] Method: Mice were immunized intra-dermally with a KLH-DTH emulsion on Day 0. Mice were dosed with either dexamethasone intraperitoneally (17ug per mouse in 100u1 of PBS) as a positive control, or orally with sucrose vehicle alone as a negative control, or with Lactococcus lactis spp. Cremoris powder resuspended in a sucrose delivery buffer or with enteric coated 2mm minitablets containing different doses of Lactococcus lactis spp. Cremoris powder (0.1mg, 0.35 mg, 1 mg, or 3.5 mg) (see Figure 1) on days 1-8.
The coating is provided in Table 5. On day 8, mice were challenged intra-dermally in the left ear with bug of KLH and 24 hours later the change in ear thickness from baseline was assessed.

[1819] Results: When delivered in enteric coated minitablets, 3.5mg and lmg doses of L. lactis spp. Cremoris powder led to a significant reduction in ear swelling compared to vehicle control.
Table 5: Enteric coating (on dry basis) on L. lactis spp. Cremoris minitablets (2mm) Component Enteric coating (mg) Enteric coating (mg/cm2 surface) EUDRAGIT L 30 D-55 0.97 6.6 Triethylcitrate 0.19 1.32 Talc 0.48 3.3 Example 3: Methacrylic acrylate copolymer coating [1820] Table 6 presents a coating suspension including Kollicoat MAE 100P
as the enteric polymer, plasticizers (1,2-propylene glycol, triethyl citrate or polyethylene glycols) ranges from 10-25% based on the polymer weight, and anti-tacking agent ranges from 15-25% based on the polymer weight.
Table 6: Kollicoat Coating Suspension Composition Excipient Function (% w/w) Kollicoat MAE 100P Enteric Polymer 15.00 Triethyl Citrate (TEC) Plasticizer 2.25 Anti-tacking Talc 3.00 agent/Pigment Water 79.75 Total 100.00 Coating Suspension Preparation Procedure a. Divided the water into three portions b. Dissolved TEC into portion 1 water (solution 1) c. Re-dispersed polymer into portion 2 water slowly, stirred with a magnetic stirring bar for 2 hrs, ensured polymer was fully hydrated/ dispersed with no lumps (suspension 2) d. Dispensed talc into portion 3 water slowly to hydrate, homogenized the talc suspension with a Silverson high shear homogenizer for 3 minutes at 6000RPM to ensure no lump (suspension 3) e. Added solution 1 into suspension 2, followed by the addition of suspension 3 f. Mixed for 15 minutes and pass the suspension through USP#60 mesh g. The final suspension was subject for coating Coating Equipment and Processing Parameters Table 7: Process 1 (Mini tablets) Coating Equipment VFC-Lab Micro Fluid Bed Batch size 20 g Nozzle diameter 0.8mm Spray rate 0.5-0.8 g/min Nozzle air 21-25 PSI
Inlet air Tm 50-55 C
Exhaust Tm 34-37 C
Pump rate 10-12 RPM
Table 8: Process 2 (Single Tablet) Coating Equipment O'hara LC M10 Pan Coater Batch size 650 g Nozzle diameter 0.8 mm Spray rate 5 g/min Atomization Air Pressure 25.4 PSI
Pattern Air Pressure 20.5 PSI
Supply Air Volume 90 cfm Inlet air Tm 47-50 C
Exhaust Tm 35-38 C
Drum Size 12 in Drum Speed 12 RPM
Example 4: Coating Tablets [1821] Tablets of Prevotella Strain B 50329 (NRRL accession number B
50329) and tablets of Veil/one/la bacteria (deposited as ATCC designation number PTA-125691) were prepared. Placebo tablets were also coated.
[1822] The tablets of Prevotella Strain B 50329 were 650 mg. Placebo tablets were also prepared.
[1823] The tablets of the Veil/one/la strain were 400 mg. Tablets were prepared in two strengths (high and low doses). Placebo tablets were also prepared.

[1824] Table 9 provides the formulation compositions of the coating suspensions.
Table 9: Formulation compositions of coating suspensions Sub-coat Top-coat (Enteric) Material Composition %
Composition % (w/w) (w/w) Kollidon MAE 10013 15.00 TEC 2.25 Talc 3.00 Additional Water 79.75 Opadry II White 15.0 Product code: 85F18422 WFI 85.0 Total 100.0 100.0 [1825] The tablets were coated as follows.
Coating Suspension Manufacturing Procedure:
1. Divided the water into two portions and dispensed part one of the water for injection into a tared stainless-steel vessel.
2. Weighed and dispensed the Triethyl Citrate into a suitable tared container.
3. Added the dispensed Triethyl Citrate to the water while mixing with the overhead stirrer.
4. Weighed and dispensed the Talc into a suitable tared container.
5. Added the dispensed Talc slowly to the water! Triethyl Citrate solution, while mixing with the overhead stirrer.
6. Once the Talc was fully hydrated, transfered the vessel to the Silverson. Homogenized for a minimum of 10 minutes, ensuring that all Talc had been fully dispersed /

homogenized, without any lumps and with no material stuck to the mixer head.
7. Dispensed Part Two of the Water for injection into a tared stainless-steel vessel.
8. Weighed and dispensed the Kollicoat into a suitable tared container.
9. Added the dispensed Kollicoat slowly to the water from step 7 while mixing with the overhead stirrer.
10. Continued mixing until all the Kollicoat had been added and is fully hydrated and dispersed without any lumps and with no material stuck to the paddle.

11. Transfered the Water/Triethyl Citrate/Talc suspension to the overhead stirrer and started mixing.
12. Whilst continuing to mix, transfered the Kollicoat suspension into the vessel. Mixed for a minimum of 45 minutes at an appropriate speed to form a vortex without any aeration.
13. Passed the coating suspension through a 5001.tm sieve into a stainless-steel vessel.
Ensured all solids passed through the mesh.
[1826] Table 10 provides the process parameters for enteric coating.
Table 10: Process Parameters of Enteric coating Active Placebo Bed Temperature ( C) 30 - 35 30 - 35 Drum Speed (rpm) 17 17 Inlet Airflow (m3/hr) 170 170- 180 Cabinet Pressure (Pa) ¨ 60 ¨ 60 Inlet Air Temperature ( C) 46 - 49 46 - 52 Atomising Air Pressure 1.6 1.6 (bar) Spray Rate 6 g/min/kg - 5.9 g/min consistent 6 g/min/kg - 5.8 g/min ¨ 1450 capsules consistent¨ 1456 tablets Distance to bed 15 cm 15 cm Angle to capsule bed 90 ¨ 15 to the bed 90 ¨ 15 to the bed Baffles No (batch too big) No (batch too big) Nozzle size 0.8 mm 0.8 mm Drum size 15" drum 15" drum Coating efficiency overall 93.5% 96.0%
[1827] Table 11 provides the disintegration results for the Prevotella Strain B 50329 (active) and placebo tablets.

Table 11: Prevotella Strain B Disintegration Results Results Batch Storage Time Point (hh:mm:ss) Reference Condition (Months) 0.1 M HCl 6.8 pH Buffer First: 00:12:56 Active DND*
Initial Last: 00:14:36 First: 00:10:21 Placebo DND
Last: 00:14:10 First: 00:13:09 Active DND
Last: 00:15:11 T= 1 month First: 00:06:21 Placebo DND
Last: 00:07:41 First: 00:12:18 Active DND
25 C, 60% Last: 00:15:18 T= 1 month RH First: 00:06:26 Placebo DND
Last: 00:08:23 First: 00:14:06 Active DND
30 C, 65% Last: 00:15:50 T= 1 month RH First: 00:07:05 Placebo DND
Last: 00:09:04 First: 00:11:47 Active DND
40 C, 75% Last: 00:13:07 T= 1 month RH First: 00:08:05 Placebo DND
Last: 00:09:16 DND*: Did not disintegrate; RH: relative humidity [1828] Table 12 provides the disintegration results for the high and low dose tablets of the Veil/one/la strain.
Table 12: Veillonella Tablets Disintegration Results Results (hh: mm: ss) Batch Storage Time Point Reference Condition (Months) 0.1 M HC1 6.8 pH Buffer Initial High Dose 2-8 C DND* 00:19:08 Initial Low Dose 2-8 C DND* 00:09:05 *DND ¨ Did not disintegrate Example 5: Coating Capsules [1829] Capsules were prepared for:
= Prevotella Strain B 50329 (NRRL accession number B 50329) = Veil/one/la bacteria (deposited as ATCC designation number PTA-125691) = Lactococcus lactis cremoris Strain A (deposited as ATCC designation number PTA-125368) = Bifidobacterium bacteria (deposited as ATCC designation number PTA-125097) [1830] The capsules were all size 0.
[1831] Capsules of the Veillonella strain were prepared in two strengths (high and low doses).
[1832] Capsules were banded with an HPMC-based banding solution prior to enteric coating.
[1833] Table 13 provides the formulation compositions of the coating suspensions.
Table 13: Composition of Coating Solutions Coating Suspension Ingredients Eudragit L30-D55 Enteric Coating Agent 39.72 USP / Ph. Eur.
Triethyl citrate Plasticizer 2.31 USP / Ph. Eur.
Talc Antiadhesive 5.78 USP / Ph. Eur.
Water for Injection' Solvent 52.19 USP / Ph. Eur.
a Removed during processing [1834] The capsules were coated as follows:
Coating Suspension Preparation Procedure:
1. Weighed and dispensed the Water for injection into a tared stainless-steel vessel.
2. Weighed and dispensed the Triethyl Citrate into a suitable tared container.
3. Weighed and dispensed the Talc into a suitable tared container.
4. Added the Triethyl Citrate and Talc to the water and dispersed by stirring gently with a palette knife until there was no talc floating on the surface of the water.
Ensured that the talc was fully wetted before commencing stirring.
5. Homogenized using the Silverson mixer for a minimum of 10 mins.
6. Weighed and dispensed the Eudragit L30-D55 into a suitable tared container.

7. Stired the Eudragit L30-D55 into the Triethyl Citrate / Talc suspension using an overhead mixer. Recorded the mixing speed. Maintained sufficient mixing to prevent further air ingress.
8. Continued mixing for a minimum of 30 minutes.
9. Passed the coating suspension through a 500[tm sieve into a second stainless steel vessel.
[1835] Table 14 provides the process parameters of enteric coating.
Table 14: Process Parameters of Enteric Coating Parameter Settings Bed Temperature ( C) 26-30 Inlet Airflow (m3/hr) 150-180 Drum Speed (RPM) 18 Cabinet Pressure (Pa) ¨ 60 Inlet Air Temperature ( C) 45 Atomising Air Pressure (bar) 1.4 Spray Rate 12 g/min/kg Distance to bed 15 cm Angle to capsule bed 90 ¨ 15 to the bed Nozzle size 0.8 mm Drum size 15" drum [1836] Table 15 provides the disintegration results for Prevotella Strain B capsules.
Table 15: Disintegration results (Prevotella Strain B) Results (hh: mm: ss) Batch Storage Time Point Reference Condition Poi 0.1 M
(Months) HC1 6.8 pH Buffer Prevotella Initial 2-8 C DND* 00:10:10 active DND*: Did not disintegrate [1837] Table 16 provides the disintegration results for the Veil/one/la strain capsules.

Table 16: Disintegration Results (Veillonella) Results (hh:mm: ss) Batch Reference Storage Time Point Condition (Months) 0.1 M HC1 6.8 pH
Buffer Low dose Initial DND* First:
00:05:42 2-8 Last:
00:07:05 C
First: 00:06:04 High dose Initial DND
Last: 00:13:28 *DND ¨ Did not disintegrate Example 6: Representative Strains As Sources for EVs [1838] Secreted microbial extracellular vesicles (smEVs) were isolated from the strains listed in Table J. Information on the Gram staining, cell wall structure, and taxonomic classification for each strain is also provided in Table J.
[1839] Bacteria of the taxonomic groups listed in Table J (e.g., class, order, family, genus, species or strain) can be used in the solid dosage forms described herein.
[1840] mEVs of bacteria of the taxonomic groups listed in Table J (e.g., class, order, family, genus, species or strain) can be used in the solid dosage forms described herein.

Table J: Strains from which extracellular vesicles (EVs) were isolated Cell Strain Gram-stain envelope Phylum Class Order Family n.) o structure w 1¨, Parabacteroides distasonis Gram-stain---...
1¨, diderm Bacteroidota Bacteroidia Bacteroidales Porphyromonadaceae c,.) DRLU022118 A ILEUM-6 negative c,.) o Gram-stain-=
Parabacteroides goldsteinii S4 diderm Bacteroidota Bacteroidia Bacteroidales Porphyromonadaceae .6.
negative Gram-stain-Prevotella histicola diderm Bacteroidota Bacteroidia Bacteroidales Prevotellaceae negative Gram-stain-Prevotella histicola diderm Bacteroidota Bacteroidia Bacteroidales Prevotellaceae negative Fournierella massiliensis S10 Gram-stain-Oscillospiraceae monoderm Firmicutes Clostridia Eubacteriales gormely GIMucosa-297 negative Ruminococcaceae) Gram-stain-Hartyffintia acetispora S4-M5 monoderm Firmicutes Clostridia Eubacteriales Oscillospiraceae P
negative .
L.

Gram-stain-.
Blautia massiliensis S1046 -4A5 monoderm Firmicutes Clostridia Eubacteriales Lachnospiraceae u, negative .3 Hediterraneibacterl[Ruminococcus] Gram-stain-r., o monoderm Firmicutes Clostridia Eubacteriales ..
Lachnospiraceae .. o o gnavus S10 GIMucosa-412 negative r.,"
, Clostridioides difficile S10 GImucosa- Gram-stain-monoderm Firmicutes Clostridia Eubacteriales Peptostreptococcaceae , 525 positive ...]
Clostridiales Family Gram-stain-XIII/Incertae sedis Amimpda sp. S16-M4 monoderm Firmicutes Clostridia Eubacteriales positive 4 1/Eubacteriales, no family]
Gram-stain-Hegasphaera sp. S29-N3 diderm Firmicutes Negatiyicutes Veillonellales Veillonellaceae negative Gram-stain-Hegasphaera sp. S1007 diderm Firmicutes Negatiyicutes Veillonellales Veillonellaceae negative IV
n Gram-stain-Selenomonas felix S34N-30OR diderm Firmicutes Negatiyicutes Selenomonadales Selenomonadaceae negative ci) Gram-stain-n.) Veillonella parvula Sl4Ileum-201 diderm Firmicutes Negatiyicutes Veillonellales Veillonellaceae negative o Gram-stain-Propionispora sp. DSM100705-1A diderm Firmicutes Negatiyicutes Selenomonadales Sporomusaceae o o negative oe n.) Gram-stain-oe Rarimicrobium hominis S24RS2-T2-5 diderm Synergistota Synergistia Synergistales Synergistaceae negative Gram-stain-Cloacibacillus evryensis S29-M8 diderm Synergistota Synergistia Synergistales Synergistaceae negative Gram-stain-Veillonella parvula S14-205 diderm Firmicutes Negativicutes Veillonellales Veillonellaceae negative n.) o Gram-stain-n.) Veillonella spl dispar ECDO 1-DP -201 diderm Firmicutes Negativicutes Veillonellales Veillonellaceae , negative Veillonella parvulal dispar ECDO 1 -DP - Gram-stain-c,.) diderm Firmicutes Negativicutes Veillonellales Veillonellaceae o 223 negative o .6.
Gram-stain-Veillonella parvula S16 GIMucosa-95 diderm Firmicutes Negativicutes Veillonellales Veillonellaceae negative P
.
L.
u, , .3 t.) r., .
o r., N) , , , .., Iv n ,-i cp w =
w =
-a-, cA
cA
oe n.) oe Example 7: Delayed-type hypersensitivity (DTH) is an animal model [1841] Delayed-type hypersensitivity (DTH) is an animal model of atopic dermatitis (or allergic contact dermatitis), as reviewed by Petersen et al. (In vivo pharmacological disease models for psoriasis and atopic dermatitis in drug discovery. Basic &
Clinical Pharm & Toxicology. 2006. 99(2): 104-115; see also Irving C. Allen (ed.) Mouse Models of Innate Immunity: Methods and Protocols, Methods in Molecular Biology, 2013.
vol.
1031, DOT 10.1007/978-1-62703-481-413). Several variations of the DTH model have been used and are well known in the art (Irving C. Allen (ed.). Mouse Models of Innate Immunity: Methods and Protocols, Methods in Molecular Biology. Vol. 1031, DOT
10.1007/978-1-62703-481-413, Springer Science + Business Media, LLC 2013).
[1842] DTH can be induced in a variety of mouse and rat strains using various haptens or antigens, for example an antigen emulsified with an adjuvant. DTH
is characterized by sensitization as well as an antigen-specific T cell-mediated reaction that results in erythema, edema, and cellular infiltration ¨ especially infiltration of antigen presenting cells (APCs), eosinophils, activated CD4+ T cells, and cytokine-expressing Th2 cells.
[1843] Generally, mice are primed with an antigen administered in the context of an adjuvant (e.g., Complete Freund's Adjuvant) in order to induce a secondary (or memory) immune response measured by swelling and antigen-specific antibody titer.
[1844] Dexamethasone, a corticosteroid, is a known anti-inflammatory that ameliorates DTH reactions in mice and serves as a positive control for suppressing inflammation in this model (Taube and Carlsten, Action of dexamethasone in the suppression of delayed-type hypersensitivity in reconstituted SCID mice.
Inflamm Res.
2000. 49(10): 548-52). For the positive control group, a stock solution of 17 mg/mL of Dexamethasone is prepared on Day 0 by diluting 6.8 mg Dexamethasone in 400 pL
96%
ethanol. For each day of dosing, a working solution is prepared by diluting the stock solution 100x in sterile PBS to obtain a final concentration of 0.17 mg/mL in a septum vial for intraperitoneal dosing. Dexamethasone-treated mice receive 100 [EL
Dexamethasone i.p.
(5 mL/kg of a 0.17 mg/mL solution). Frozen sucrose serves as the negative control (vehicle).
[1845] Solid dosage forms are tested for their efficacy in the mouse model of DTH, either alone or in combination, with or without the addition of other anti-inflammatory treatments. For example, 6-8 week old C57B1/6 mice are obtained from Taconic (Germantown, NY), or other vendor. Groups of mice are administered four subcutaneous (s.c.) injections at four sites on the back (upper and lower) of antigen (e.g., Ovalbumin (OVA) or Keyhole Limpet Hemocyanin (KLH)) in an effective dose (e.g., 50u1 total volume per site). For a DTH response, animals are injected intradermally (i.d.) in the ears under ketamine/xylazine anesthesia (approximately 50mg/kg and 5 mg/kg, respectively).
Some mice serve as control animals. Some groups of mice are challenged with lOul per ear (vehicle control (0.01% DMSO in saline) in the left ear and antigen (21.2 ug (12nmol) in the right ear) on day 8. To measure ear inflammation, the ear thickness of manually restrained animals is measured using a Mitutoyo micrometer. The ear thickness is measured before intradermal challenge as the baseline level for each individual animal.
Subsequently, the ear thickness is measured two times after intradermal challenge, at approximately 24 hours and 48 hours (i.e., days 9 and 10).
[1846] Treatment with a solid dosage form is initiated at some point, either around the time of priming or around the time of DTH challenge. For example, a solid dosage form may be administered at the same time as the subcutaneous injections (day 0), or it may be administered prior to, or upon, intradermal injection. A solid dosage form is administered (e.g., orally) at varied doses and at defined intervals. Examples are provided in the above examples. Some mice may receive a solid dosage form every day (e.g., starting on day 0), while others may receive a solid dosage form at alternative intervals (e.g., every other day, or once every three days).
[1847] As an example, an emulsion of Keyhole Limpet Hemocyanin (KLH) and Complete Freund's Adjuvant (CFA) can be prepared freshly on the day of immunization (day 0). To this end, 8 mg of KLH powder is weighed and is thoroughly re-suspended in 16 mL saline. An emulsion is prepared by mixing the KLH/saline with an equal volume of CFA solution (e.g., 10 mL KLH/saline + 10 mL CFA solution) using syringes and a luer lock connector. KLH and CFA are mixed vigorously for several minutes to form a white-colored emulsion to obtain maximum stability. A drop test is performed to check if a homogenous emulsion is obtained.
[1848] On day 0, C57B1/6J female mice, approximately 7 weeks old, are primed with KLH antigen in CFA by subcutaneous immunization (4 sites, 50 [IL per site). A solid dosage form is administered as described herein.

[1849] On day 8, mice are challenged intradermally (i.d.) with 10 pg KLH
in saline (in a volume of 10 [IL) in the left ear. Ear pinna thickness is measured at 24 hours following antigen challenge. The effectiveness of a solid dosage form at suppressing inflammation is determined by ear thickness.
[1850] For future inflammation studies, some groups of mice may be treated with anti-inflammatory agent(s) (e.g., anti-CD154, blockade of members of the TNF
family, or other treatment), and/or an appropriate control (e.g., vehicle or control antibody) at various timepoints and at effective doses.
[1851] At various timepoints, serum samples may be taken. Other groups of mice may be sacrificed and lymph nodes, spleen, mesenteric lymph nodes (MLN), the small intestine, colon, and other tissues may be removed for histology studies, ex vivo histological, cytokine and/or flow cytometric analysis using methods known in the art.
Some mice are exsanguinated from the orbital plexus under 02/CO2 anesthesia and ELISA
assays performed.
[1852] Tissues may be dissociated using dissociation enzymes according to the manufacturer's instructions. Cells are stained for analysis by flow cytometry using techniques known in the art. Staining antibodies can include anti-CD11 c (dendritic cells), anti-CD80, anti-CD86, anti-CD40, anti-MHCII, anti-CD8a, anti-CD4, and anti-CD103.
Other markers that may be analyzed include pan-immune cell marker CD45, T cell markers (CD3, CD4, CD8, CD25, Foxp3, T-bet, Gata3, Rory-gamma-t, Granzyme B, CD69, PD-1, CTLA-4), and macrophage/myeloid markers (CD11b, MHCII, CD206, CD40, CSF1R, PD-L1, Gr-1, F4/80). In addition to immunophenotyping, serum cytokines can be analyzed including, but not limited to, TNFa, IL-17, IL-13, IL-12p70, IL12p40, IL-10, IL-6, IL-5, IL-4, IL-2, IL-lb, IFNy, GM-CSF, G-CSF, M-CSF, MIG, IP10, MIP1b, RANTES, and MCP-1. Cytokine analysis may be carried out on immune cells obtained from lymph nodes or other tissue, and/or on purified CD45+ infiltrated immune cells obtained ex vivo. Finally, immunohistochemistry is carried out on various tissue sections to measure T
cells, macrophages, dendritic cells, and checkpoint molecule protein expression.
[1853] Ears may be removed from the sacrificed animals and placed in cold EDTA-free protease inhibitor cocktail (Roche). Ears are homogenized using bead disruption and supernatants analyzed for various cytokines by Luminex kit (EMD Millipore) as per manufacturer's instructions. In addition, cervical lymph nodes are dissociated through a cell strainer, washed, and stained for FoxP3 (PE-FJK-165) and CD25 (FITC-PC61.5) using methods known in the art.
[1854] In order to examine the impact and longevity of DTH protection, rather than being sacrificed, some mice may be rechallenged with the challenging antigen at a later time and mice analyzed for susceptibility to DTH and severity of response.
Example 7: Oral Administration [1855] A subject can self-administer a solid dosage form orally in the morning with water, refraining from consuming acidic drinks 1 hour either side of dosing and from eating 2 hours before dosing and 1 hour after dosing.
Incorporation by Reference [1856] All publications patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
Equivalents [1857] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim:

1. A solid dosage form comprising a pharmaceutical agent, wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form is enterically coated.

2. The solid dose form of claim 1, wherein the solid dose form is for oral administration and/or for therapeutic use.

3. The solid dose form of claim 1 or claim 2 comprising a therapeutically effective amount of the pharmaceutical agent.

4. The solid dosage form of any one of claims 1 to 3, wherein the solid dosage form comprises a capsule.

5. The solid dosage form of claim 4, wherein the enterically coated capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.

6. The solid dosage form of claim 1, wherein the solid dosage form comprises an enterically coated tablet.

7. The solid dosage form of claim 6, wherein the enterically coated tablet is a 5mm, 6mm, 7mm, 8mm, 9mm, lOmm, llmm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, or 18mm tablet.

8. The solid dosage form of claim 1, wherein the solid dosage form comprises a minitablet.

9. The solid dosage form of claim 8, wherein the minitablet is a lmm minitablet, 1.5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet.

10. The solid dosage form of claim 8 or 9, wherein a plurality of minitablets are contained in a capsule.

11. The solid dosage form of claim 10, wherein the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.

12. The solid dosage form of claim 11, wherein the capsule is a size 0 capsule.

13. The solid dosage form of claim 12, wherein the size 0 capsule comprises minitablets.

14. The solid dosage form of claim 13, wherein the capsule comprises about minitablets.

15. The solid dosage form of any one of claims 8 to 14, wherein the minitablets are 3mm minitablets.

16. The solid dosage form of any one of claims 8 to 15, wherein the capsule comprises HPMC (hydroxyl propyl methyl cellulose) or gelatin.

17. The solid dosage form of any one of claims 1 to 6, wherein the enteric coating comprises one enteric coating.

18. The solid dosage form of any one of claims 1 to 17, wherein the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings do not contain identical components in identical amounts.

19. The solid dosage form of claim any one of claims 1 to 18, wherein the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

20. The solid dosage form of claim any one of claims 1 to 19, wherein the enteric coating comprises one enteric coating which comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

21. The solid dosage form of any one of claims 1 to 20, wherein the enteric coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

22. The solid dosage form of any one of claims 1 to 21, wherein the enteric coating comprises an anionic polymeric material.

23. The solid dosage form of any one of claims 1 to 22, wherein the pharmaceutical agent comprises bacteria.

24. The solid dosage form of any one of claims 1 to 23, wherein the pharmaceutical agent comprises microbial extracellular vesicles (mEV).

25. The solid dosage form of any one of claims 1 to 24, wherein the pharmaceutical agent comprises isolated bacteria.

26. The solid dosage form of any one of claims 23 to25, wherein at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is the bacteria.

27. The solid dosage form of any one of claims 23 to 26, wherein the bacteria comprise bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

28. The solid dosage form of any one of claims 23 to 27, wherein the bacteria comprise live bacteria.

29. The solid dosage form of any one of claims 23 to 28, wherein the bacteria comprise dead bacteria.

30. The solid dosage form of any one of claims 23 to 29, wherein the bacteria comprise non-replicating bacteria.

31. The solid dosage form of any one of claims 23 to 30, wherein the bacteria are from one strain of bacteria.

32. The solid dosage form of any one of claims 23 to 31, wherein the bacteria are lyophilized.

33. The solid dosage form of claim 32, wherein the lyophilized bacteria are in admixture with a pharmaceutically acceptable excipient.

34. The solid dosage form of any one of claims 23 to 33, wherein the bacteria are gamma irradiated.

35. The solid dosage form of any one of claims 23 to 34, wherein the bacteria are UV
irradiated.

36. The solid dosage form of any one of claims 23 to 35, wherein the bacteria are heat inactivated.

37. The solid dosage form of claim 36, wherein the bacteria are heat inactivated at about 50 C for at least two hours or at about 90 C for at least two hours.

38. The solid dosage form of any one of claims 23 to 37, wherein the bacteria are acid treated.

39. The solid dosage form of any one of claims 23 to 38, wherein the bacteria are oxygen sparged.

40. The solid dosage form of claim 39, wherein the bacteria are oxygen sparged at 0.1 vvm for two hours.

41. The solid dosage form of any one of claims 23 to 40, wherein the bacteria are Gram positive bacteria.

42. The solid dosage form of any one of claims 23 to 40, wherein the bacteria are Gram negative bacteria.

43. The solid dosage form of any one of claims 23 to 42, wherein the bacteria are aerobic bacteria.

44. The solid dosage form of any one of claims 23 to 42, wherein the bacteria are anaerobic bacteria.

45. The solid dosage form of any one of claims 23 to 44, wherein the bacteria are acidophile bacteria.

46. The solid dosage form of any one of claims 23 to 44, wherein the bacteria are alkaliphile bacteria.

47. The solid dosage form of any one of claims 23 to 44, wherein the bacteria are neutralophile bacteria.

48. The solid dosage form of any one of claims 23 to 47, wherein the bacteria are fastidious bacteria.

49. The solid dosage form of any one of claims 23 to 47, wherein the bacteria are nonfastidious bacteria.

50. The solid dosage form of any one of claims 23 to 49, wherein the bacteria are from a class, order, family, genus, species and/or strain listed in Table 1, Table 2, or Table 3.

51. The solid dosage form of claim 50, wherein the bacteria are from a bacterial strain listed in Table 1, Table 2, or Table 3.

52. The solid dosage form of any one of claims 23 to 51, wherein the bacteria are from bacteria from a class, order, family, genus, species and/or strain listed in Table J.

53. The solid dosage form of claim 52, wherein the bacteria are from a bacterial strain listed in Table J.

54. The solid dosage form of any one of claims 1 to 22, wherein the pharmaceutical agent comprises isolated mEVs.

55. The solid dosage form of claim 54 comprising a therapeutically effective amount of the isolated mEVs.

56. The solid dosage form of claim 54 or 55, wherein at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical agent is the isolated mEVs.

57. The solid dosage form of any one of claims 54 to 56, wherein the mEVs comprise secreted mEVs (smEVs).

58. The solid dosage form of any one of claims 54 to 57, wherein the mEVs comprise processed mEVs (pmEVs).

59. The solid dosage form of claim 58, wherein the pmEVs are produced from bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

60. The solid dosage form of claims 58 or 59, wherein the pmEVs are produced from live bacteria.

61. The solid dosage form of claims 58 or 59, wherein the pmEVs are produced from dead bacteria.

62. The solid dosage form of claims 58 or 59, wherein the pmEVs are produced from non-replicating bacteria.

63. The solid dosage form of any one of claims 54 to 62, wherein the mEVs are from one strain of bacteria.

64. The solid dosage form of any one of claims 54 to 63, wherein the mEVs are lyophilized.

65. The solid dosage form of claim 64, wherein the lyophilized mEVs are in admixture with a pharmaceutically acceptable excipient).

66. The solid dosage form of any one of claims 54 to 65, wherein the mEVs are gamma irradiated.

67. The solid dosage form of any one of claims 54 to 66, wherein the mEVs are UV
irradiated.

68. The solid dosage form of any one of claims 54 to 67, wherein the mEVs are heat inactivated.

69. The solid dosage form of claim 68, wherein the mEVs are heat inactivated at about 50 C for at least two hours or at about 90 C for at least two hours.

70. The solid dosage form of any one of claims 54 to 69, wherein the mEVs are acid treated.

71. The solid dosage form of any one of claims 54 to 70, wherein the mEVs are oxygen sparged.

72. The solid dosage form of claim 71, wherein the mEVs are oxygen sparged at 0.1 vvm for two hours.

73. The solid dosage form of any one of claims 54 to 72, wherein the mEVs are from Gram positive bacteria.

74. The solid dosage form of any one of claims 54 to 72, wherein the mEVs are from Gram negative bacteria.

75. The solid dosage form of any one of claims 45 to 74, wherein the mEVs are from aerobic bacteria.

76. The solid dosage form of any one of claims 54 to 74, wherein the mEVs are from anaerobic bacteria.

77. The solid dosage form of any one of claims 54 to 76, wherein the mEVs are from acidophile bacteria.

78. The solid dosage form of any one of claims 54 to 76, wherein the mEVs are from alkaliphile bacteria.

79. The solid dosage form of any one of claims 54 to 76, wherein the mEVs are from neutral ophile bacteria.

80. The solid dosage form of any one of claims 54 to 79, wherein the mEVs are from fastidious bacteria.

81. The solid dosage form of any one of claims 54 to 79, wherein the mEVs are from nonfastidious bacteria.

82. The solid dosage form of any one of claims 54 to 81, wherein the mEVs are from bacteria of a class, order, family, genus, species and/or strain listed in Table 1, Table 2, or Table 3.

83. The solid dosage form claim 82, wherein the mEVs are from a bacterial strain listed in Table 1, Table 2, or Table 3.

84. The solid dosage form of any one of claims 54 to 83, wherein the mEVs are from bacteria of a class, order, family, genus, species and/or strain listed in Table J.

85. The solid dosage form of claim 84, wherein the mEVs are from a bacterial strain listed in Table J.

86. The solid dosage form of any one of claims 23 to 53, wherein the dose of bacteria is about 1 x 107 to about 2 x 1012 cells, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

87. The solid dosage form of claim 86, wherein the dose of bacteria is about 3 x 1010 or about 1.5 x 1011or about 1.5 x 1012.

88. The solid dosage form of claim 86, wherein the pharmaceutical agent comprises bacteria and the dose of bacteria is about 1 x 109, about 3 x 109, about 5 x 109, about 1.5 x 1010, about 3 x 1010, about 5 x 1010, about 1.5 x 1011, about 1.5 x 1012, or about 2 x 1012 cells, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

89. The solid dosage form of any one of claims 1 to 88, wherein the dose of the pharmaceutical agent is about 10 mg to about 1500 mg, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

90. The solid dosage form of any one of claims 1 to 88, wherein the dose of the pharmaceutical agent is about 30 mg to about 1300 mg by weight, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

91. The solid dosage form of claim 90, wherein the dose is about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule

92. The solid dosage form of any one of claims 1 to 88, wherein the dose of the pharmaceutical agent is about 2x106 to about 2x10'6 particles, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

93. The solid dosage form of claim 92, wherein particle count is determined by nanoparticle tracking analysis (NTA).

94. The solid dosage form of any one of claims 1 to 88, wherein the dose of the pharmaceutical agent is about 5 mg to about 900 mg total protein, wherein the dose is per capsule or tablet or per total number of minitablets in a capsule.

95. The solid dosage form of claim 94, wherein total protein is determined by Bradford assay or by BCA.

96. The solid dosage form of any one of claims 1 to 95, wherein the solid dosage form further comprises one or more additional pharmaceutical agents.

97. The solid dosage form of any one of claims 1 to 96, wherein the solid dosage form further comprises an excipient.

98. The solid dosage form of claim 97, wherein the excipient is a diluent, a binder and/or an adhesive, a disintegrant, a lubricant and/or a glidant, a coloring agent, a flavoring agent, and/or a sweetening agent.

99. A method of treating a subject, the method comprising administering to the subject a solid dosage form of any one of claims 1 to 98.

100. The solid dosage form of any one of claims 1 to 98 for use in treating a subject.

101. Use of a solid dosage form of any one of claims 1 to 98 for the preparation of a medicament for treating a subject.

102. The method, solid dosage form, or use of any one of claims 99 to 101, wherein the solid dosage form is orally administered.

103. The method, solid dosage form, or use of any one of claims 99 to 102, wherein the solid dosage form is administered on an empty stomach.

104. The method, solid dosage form, or use of any one of claims 99 to 103, wherein the solid dosage form is administered 1, 2, 3, or 4 times a day.

105. The method, solid dosage form, or use of any one of claims 99 to 104, wherein the solid dosage form comprises a tablet or a plurality of minitablets within a capsule, and 1, 2, 3, or 4 solid dosage forms are administered 1, 2, 3, or 4 times a day.

106. The method, solid dosage form, or use of any one of claims 99 to 105, wherein the subject is in need of treatment and/or prevention of a cancer.

107. The method, solid dosage form, or use of any one of claims 99 to 105, wherein the subject is in need of treatment and/or prevention of an autoimmune disease.

108. The method, solid dosage form, or use of any one of claims 99 to 105, wherein the subject is in need of treatment and/or prevention of an inflammatory disease.

109. The method, solid dosage form, or use of any one of claims 99 to 105, wherein the subject is in need of treatment and/or prevention of a metabolic disease.

110. The method, solid dosage form, or use of any one of claims 99 to 105, wherein the subject is in need of treatment and/or prevention of dysbiosis.

111. The method, solid dosage form, or use of any one of claims 99 to 110, wherein the solid dosage form is administered in combination with an additional pharmaceutical agent.

112. A method for preparing an enterically coated capsule comprising a pharmaceutical agent, wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
b) loading the pharmaceutical agent and pharmaceutically acceptable excipient into a capsule; and c) enterically coating the capsule, thereby preparing the enterically coated capsule.

113 The method of claim 112, wherein the method comprises combining the pharmaceutical agent with a pharmaceutically acceptable excipient prior to loading into the cap sule.

114. The method of claim 112, wherein the method comprises banding the capsule after loading the capsule and prior to enterically coating the capsule.

115. A method for preparing an enterically coated tablet comprising a pharmaceutical agent, wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a tablet; and c) enterically coating the tablet, thereby preparing an enterically coated tablet.

116. A method for preparing an enterically coated minitablet comprising a pharmaceutical agent, wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a minitablet; and c) enterically coating the minitablet, thereby preparing the enterically coated minitablet.

117. The method of claim 116, wherein the minitablet is loaded into a capsule.

118. A method for preparing a capsule comprising enterically coated minitablets comprising a pharmaceutical agent, wherein the pharmaceutical agent comprises bacteria and/or microbial extracellular vesicles (mEVs), the method comprising:
a) combining the pharmaceutical agent with a pharmaceutically acceptable excipient;
b) compressing the pharmaceutical agent and pharmaceutically acceptable excipient, thereby forming a minitablet;
c) enterically coating the minitablet, thereby preparing an enterically coated minitablet, and d) loading the capsule with one or more enterically coated minitablets, thereby preparing the capsule.

119. The method of any one of claims 112 to 118, wherein the pharmaceutical agent comprises a therapeutically effective amount of bacteria and/or mEVs.